Công nghệ Hóa học - Organic synthesis workbook 111

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1. T. Kinzel , F. Major, C. Raith , T. Redert, G?WllEY-VCH F. Stecker, N. Tólle , J. Zinngrebe Organic Synthesis Workbook 111 Foreword by Matthias Beller
2. Tom Kinzel, Felix Major, Thomas Redert, FIarían 5tecker, Julia Zinngrebe, Nina Talle, and Christian Raith Organic Synthesis Workbook 111
3. 1807-2007 Knowledge for Generations Each generation has its unique needs and aspirations. When Charles Wiley first opened his small printing shop in lower Manhattan in 1807, it was a generation of boundless potential searching for an identity. And we were there, helping to defme a new American literary tradition. Over half a century later, in the midst of the Second Industrial Revolution, it was a generation focused on building the future. Once again, we were there, supplying the critical scientific, technical, and engineering knowledge that helped frame the world. Throughout the 20th Century, and into the new millennium, nations began to reach out beyond their own borders and a new international community was born. Wiley was there, expanding its operations around the world to enable a global exchange of ideas, opinions, and know-how. For 200 years, Wiley has been an integral part of each generation s journey, en­ abling the flow of information and understanding necessary to meet their needs and fulfill their aspirations. Today, bold new technologies are changing the way we live and learn. Wiley will be there, providing you the must-have knowledge you need to imagine new worlds, new possibilities, and new opportunities. Generations come and go, but you can always count on Wiley to provide you the knowledge you need, when and where you need it! a ~~ William J. Pesce Peter Booth Wiley President and Chief Executive Officer Chairman of the Board
4. Tom Kinzel, Felix Major, Thomas Redert, Florian Stecker, Julia Zinngrebe, Nina Talle, and Christian Raith Organic Synthesis Workbook 111 BICENTENNIAL .J • i 1 8 o 7 ~ z z ~z @WILEY z~ ~ 2007 ~ - > • r WI LEY-VCH Verlag GmbH & Co. KGaA
5. The Authors All books published by Wiley-VCH are care­ ful1y produced. Nevertheless, authors, editors, Tom Kinzel, Felix Major, Thomas Redert, and publisher do not warrant the information F/orian Stecker, Julia Zinngrebe, Nina Tlille, contained in these books, including this Christian Raith book, to be free of errors. Readers are advised U niversity of Giittingen to keep in mind that statements, data, illus­ Institute for Organic and Biomolecular trations, procedural detalls or other items Chemistry may inadvertently be inaccurate. Tammannstr. 2 37077 Giittingen Library of Congress Card No.: Applied for Germany British Library Cataloguing-in-Publication Data: A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek Die Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbiblio­ grafie; detailed bibliographic data are avail­ able in the Internet at . © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of trans­ lation into other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into a machine language without written permis­ sion from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Printing Strauss GmbH, Miirlenbach Bookbinding Litges & Dopf GmbH, Heppenheim Cover Anne Christine Kegler, Grafik-Designerin, Karlsruhe Wiley Bicentennial Logo Richard J. Paófico Printed in the Federal Republic of Germany. Printed on aód-free papero ISBN: 978-3-527-31665-6
6. The Authors Tom IGnzel, born in 1977 in Erfurt, Germany, started studying chemistry at the University of Giittingen, Ger­ many, in October 1998. After staying in the Peoples Repub­ lic of China in 2001/2002 studying Chinese at the Univer­ sity ofNanjing and joining the working group ofProfessor Wolfgang Hennig at the Chinese Academy of Sciences in Shanghai, he returned to Giittingen and received his diplo­ ma in Chemistry in July 2004. He is now a doctoral re­ searcher in the research group of Professor Lutz F. Tietze and employs experimental and theoretical techniques for mechanistic studies and method development in the field of stereoselective homoallylic ether synthesis. Dr. Felix Major, born in 1977 in Wittmund, Germany, started studying chemistry at the University of Giittin­ gen, Germany, in October 1998. After joining the group of Professor Jonathan Clayden at the University of Manchester for three months in 2002 he returned to Giittingen and accomplished his diploma in Septem­ ber 2003 under the guidance ofProfessor Lutz F. Tietze. In November 2006, he gained his doctorate in the same research group with a thesis on the synthesis and biolo­ gical evaluation of prodrug analogues of the antibiotic CC-1065 for a selective treatment of cancer. Christian Raith was born in 1980 in Giittingen, Ger­ many, and started studying chemistry at the University of Giittingen, Germany, in October 2001. He joined the research group of Professor Lutz F. Tietze in May 2005 and received his diploma in January 2006. He is now doing his doctoral research in the same group studying palladium-catalyzed enantioselective domino­ reactions for the synthesis of chromanes. Organic Synthesis Workbook 1JI. Tom Kinzel. Felix Major, Thomas Redert, Florian Stecker, Julia Zinngrebe, Nina Tolle. Christian Raith Copyright © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31665-6
7. Thomas Redert, bom in 1978 in Gieí?en, Germany, started studying chemistry at the University of Gottin­ gen, Germany, in October 1999. After staying in the United Kingdom in 2002/2003 at the University ofNew­ castle upon Tyne and joining the working group of Dr. Julian G. Knight, he retumed to Gottingen and received his diploma in chemistry in July 2004. He is currently a doctoral researcher at the University of Gottingen in the research group of Prof. Lutz F. Tietze. His research deals with the application of Palladium-catalyzed domi­ nocyclizations for the synthesis of natural product ana­ logues. FIorían Stecker, bom in 1980 in Eutin, Germany, re­ ceived his diploma in organic chemistry from the Uni­ versity of Gottingen, Germany, in July 2004. He started studying chemistry in Gottingen in October 1999 and worked at the Université Pierre et Marie Curie, Paris VI, France, under the direction of Professor Max MaIa­ cria in 2002/2003. Shortly thereafter, he joined the group of Professor Lutz F. Tietze in Gottingen, where he is currently a doctoral researcher. He is committed to the palladium catalyzed domino-Wacker-Heck reac­ tion for the enantioselective synthesis of vitamin E and other closely related chromanes and chromenes. Nina Tolle, bom in 1981 in Osnabrück, Germany, started studying chemistry at the University of Gottin­ gen, Germany, in 2001. She joined the research group of Professor Tietze in 2005 and received her diploma in 2006. She stayed in the same group for her doctoral research which deals with Lewis-acid mediated domino­ reactions for the synthesis of spiroamine structures with the objective of natural product synthesis. Dr. Julia Zinngrebe, bom in 1979 in Eschwege, Ger­ many, started studying chemistry at the University of Gottingen, Germany, in October 1998. After joining the group of Professor Clayden at the University of Manchester for three months in 2002 she returned to Gottingen and accomplished her diploma in September 2003 under the guidance of Professor Tietze. In January 2007, she gained her doctorate in the same research group with a thesis on Palladium-catalyzed domino-re­ actions for the enantioselective synthesis of Vitamin E.
8. Dedicated to our PhD supervisor Pro! Dr. Dr. h. c. L. F. Tietze on the occasion ofhis 65th birthday
9. Foreword Organic synthesis is at the heart of chemistry. Although today interdisciplinary areas between chemistry and biology or between chemistry and material sciences are ofien believed to provide the main driving forces for the advancement of chemistry, I am convinced that the development of efficient and environmentally benign synthetic methods is still one of the most important goals of current chemical research. Significantly, a majority of all chemists doing research in industry or academia are faced in their daily lives with demands for the efficient synthesis of new molecules. It is thus important to attract the interest of talented students for this area and to provide high quality education. From the beginning, the Organic Synthesis Workbook has been devoted to a significant extent to the training and education of students and younger researchers in this direction. The main concept is to present challenging synthetic problems to the reader, which are selected from state-of-the-art syntheses of natural products. The present 3rd volume successfully follows this track. The new Organic Synthesis Workbook - similar to its predecessors - has been carefully devised and realized by a group of creative young students from the Institute of Organic and Bio­ molecular Chemistry ofthe Georg-August-University ofGottingen, Germany.1t covers 14 well­ selected synthetic problems including modern catalytic coupling reactions and metathesis chemistry, together with recent developments in stereoselective carbon-carbon and carbon­ oxygen bond formation. More specifically, each problem is introduced to the reader in a general marmer. Afier this introduction the key chemistry of the respective synthesis is explained. Then, the various synthetic problems are presented in a clear and understandable manner. The major difference to classical teaching books is the active interaction ofthe reader with the content. One could ask, is the concept ofthis book still timely? In my opinion, definitely yes! Obviously, information pours out from all kinds of scientific journals, PowerPoint presentations, and especially the internet. However, to acquire long-Iasting knowledge of organic synthesis, and to transfer this knowledge, it is essential not only to consume facts and data but to apply it to real synthetic problems. Thus, in addition to students for Masters and PhD degrees, everyone interested in synthetic chemistry is encouraged to train actively with books such as this. Finally, 1 wish to congratulate the authors for their excellent achievement. It remains for me to hope that readers will enjoy working with this volume and discover aspects that will stimulate their own future research. Matthias Beller Rostock, 20.11.2006
10. Preface In 1998, eight members ofthe research group ofProf. L. F. Tietze at the University ofGottingen, Germany, contributed to the Organic Synthesis Workbook, which was published by Wiley-VCH. The successor, Organic Synthesis Workbook JI, was published in 2001. Encouraged by the success ofthese two books we decided to write the sequel, the Organic Synthesis Workbook 111. This book contains 14 independent chapters, which are based on outstanding natural product total syntheses which were published between 2002 and 2006. We have not changed the tested original concept ofthe book, but have included a new part in each chapter, the Key Chemistry. In this subchapter we want to introduce the reader to the key chemistry ofthis total synthesis, not in a textbook-like fashion but summarizing the important facts. The natural product total syntheses were chosen according to their key step, covering modem synthetic methods as well as basic organic chemistry and industrial-scale chemistry. Each chapter starts with the Introduction presenting the target mo1ecu1e and its background followed by the Key Chemistry. The Overview shows the complete synthetic strategy on two pages. In the Synthesis section each individual Problem is presented followed by Hints to guide the reader to the right Solution. Each hint will reveal more and more of the solution; therefore it might be useful to cover the remaining page with a piece of papero In the solution the right answer is presented, giving either product or reagents and reaction conditions. Each problem ends with the Discussion, where the problem is explained in detail. After the complete synthesis the Conclusion surnmarizes the whole total synthesis high1ighting the most interesting steps. The References section includes not only the original references of the total synthesis but a1so those of the Key Chemistry section, to pro vide easy access to further information. We are very grateful for the support and encouragement we received while writing this book, in particular to our PhD advisor Prof. L. F. Tietze. The authors ofthe Organic Synthesis Workbook and the Organic Synthesis Workbook 11 who made this sequel possible are J. A. Gewert, J. Gorlitzer, S. Gotze, J. Looft, P. Menningen, T. Nobel, H. Schirock and C. Wulff, as well as C. Bittner, A. S. Busemann, U. Griesbach, F. Haunert, W.-R. Krahnert, A. Modi, J.Olschimke and P. Steck. TomKinzel Felix Major Christian Raith Thomas Redert FIorian Stecker Nina Tolle Julia Zinngrebe Gottingen, January 2007
11. Contents Chapter 1 t\ 1 Mienfiensine O::tLr'0H N~, ~ (Ovennan 2005) HN~ Key Chemistry: Enantioselective Heck Reactions Chapter 2 21 Myriaporone 4 (Taylor 1998,2004) Key Chemistry: Evans Aldol Reactions Chapter 3 41 Ningalin D (Boger 2005) HO Key Chemistry: Pyrrole Synthesis using a 1,2,4,5-Tetrazine ~ 1,2-Diazine ~ Pyrrole Strategy Chapter4 59 BIRT-377 (Barbas 2005) Key Chemistry: Organocatalysis Chapter 5 77 Vitamin E (Tietze 2006) Key Chemistry: Palladium(II)-catalyzed Domino Wacker-Heck Reaction
12. Chapter 6 93 (+)-Cyanthiwigin U (Phillips 2005, Palomo 2002) Key Chemistry: Alkene Metathesis Chapter7 113 ZK-EPO (Schering AG 2006) Key Chemistry: Macrolactonization Chapter 8 139 (+)-Laurenine (Boeckmann 2002) Key Chemistry: Enantioselective Reduction ofKetones Chapter 9 157 Cylindramide (Laschat 2005) Key Chemistry: Oxidation ofketones to the corresponding u,~-unsaturated carbonyl compounds via the silyl enol ether Chapter 10 175 Peridinin (Bruckner 2006) ACO~~~ o Key Chemistry: Formation of C=C double bonds
13. Chapter 11 193 Laulimalide (Mulzer 2003) Key Chemistry: Asyrnmetric Epoxidation of Alkenes Chapter 12 217 Cystothiazole B (Panek 2004) Key Chemistry: Stereoselective Crotylation of Aldehydes with Chiral Crotyl Silanes Chapter 13 233 (+)-Pentacycloanammoxic acid (Corey 2006) Key Chemistry: Photochemical Cycloadditions Chapter 14 253 (-)-Dactylolide o (McLeod 2006) Key Chemistry: [3,3]-Sigmatropic Ireland-Claisen Rearrangement Abbreviations 277 Index 279
14. ~ ~OH N:., ::. HN~ 1 Minfiensine (Overman 2005) 1.1 Introduction Minfiensine (1) was first isolated by Massiot and coworkers in 1989 ;\ from Strychnos minfiensisi, S. potatorum and S. longcaudata. 1 The Ccf1r"0H N~, ó unique 1,2,3,4-tetrahydro-9a,4a-(iminoethano )-9H-carbazole motif (4) HN~ is also present in related alkaloids/ exemplified by 2 and 3, which are composed of tryptamine and monoterpene units, presumably being Minfiensine derived in nature from cyc1ization of corynantheine derivatives.3 As several biological activities have been associated with these alka- ~ HO~02Me 10ids,2.4 inc1uding promising anticancer activity, a concise, enantio­ selective chemical synthesis entry to the unique structural motif 4 Q::Wy I W'­ Me I OH would allow further exploration of the pharmacology of this interest­ Me ing c1ass of alkaloids. 2 (Hydroiminoethano)-9H-carbazoles 4 having a 1,2 or 2,3 double bond Echitamine were seen as potentially versatile platforms for constructing alkaloids C0 Me of this type, as a bridging ethylideneethano unit between the pyr­ 2 rolidine nitrogen and C-2 or C-3 would form the pentacyc1ic ring Meo'Ccib~ N -'~ 5 I N skeleton found in these alkaloids. Me This chapter is based on an approach by Overman and coworkers who 3 completed the first enantioselective total synthesis of (+ )-minfiensine Vincorine (1) in 2005.5 9a,);\' 2 CcW1,& 4a N~, 3 H N H 4 1,2,3,4-tetrahydro-9a,4a­ (iminoethano)-9H-carbazole
15. 2 1 Minfiensine 1.2 Key Chemistry: Enantioselective Heck Reactions Mizorok¡.fJa and Heck6b reported independently in the early 1970s the The Heck reaction frrst palladium-mediated coupling of an aryl or vinyl halide or triflate with an aIkene. This reaction is generally referred to as the Heck reaction. From the first reports on asymmetric intramolecular Heck R1: aryl, alkyl reactions by Overman7 and Shibasaki8 in 1989 the asymmetric Heck x: 1, Br, CI, OTf (=OSO,CF ) 3 reaction has emerged as a reliable method for the stereoselective formation of tertiary and quatemary stereogenic centers by C-C bond Ovennan"s first asymmetric Heck reaction formation in polyfunctionalized molecules.9,1O,11 The basic mechanism ofthe Heck reaction (as shown below) of aryl or °rOTf Pd(OAc), (10 mol-%) (R,R)-DIOP (10 mol-%) Oi1 _ aIkenyl halides or triflates involves initial oxidative addition of a pal­ Et3N, benzene, r.t. ,.-' ladium(O) species to afford a a-arylpalladium(I1) complex 111. The 90 %, 45 % ee order of reactivity for the oxidative addition step is 1 > OTf> Br > Cl. ~ Coordination of an aIkene IV and subsequent carbon-carbon bond Shibasakts first group-selective Heck reaction formation by syn addition provide a a-alkylpalladium(I1) intermediate Pd(OAc), (3 mol-%) VI, which readily undergoes ~-hydride elimination to release the (R)-BINAP (9 mol-%) product VIII. A base is required for conversion of the hydridopalla­ C~Me cyclohexene (6 mol-%) ~e cYJ,y I ~ dium(I1) complex IX to the active palladium(O) catalyst I to complete 9 I Ag2C03 (2 equiv.) ~ A ¿ NMP, 69'C the catalytic cycle. 74%,46% ee Base' HX [Pd(O)L2] reductive ~ (R~t oxidative Base~ I elimination ~ addition [H-Pd(II)L2-X] R1-Pd(II)L2-X 111 R~~2 ::¡IX ~R2 r: IV syn f3-hydride coordination elimination 1 H:\__ ld(II)L 2-X R -Pd(II)L2-X 1 2 -== R R R2 VII V internal /.yn insertion rotatio~ R}_ld(II)L2-X H R2 VI R1 = alkenyl, aryl, benzyl, alkynyl R2 = alkenyl, aryl, alkyl, C02R', OR', SiR'3 X = 1, Br, CI, OS02CF3, S02CI, COCI, 1+(OAc), OS02F, OPO(ORh
16. 1 Minjiensine 3 A variety of palladium(I1) and palladium(O) complexes serve as effec­ tive precatalysts or precursors to the active palladium(O) catalyst. The most commonly used precatalysts in Heck chemistry are Pd(OAc)z, Pd2(dba)3, and PdCh(PPh )z. Typical catalyst loading is in the range of 3 Hemnann-Beller catalyst 5-10 mol-%. The discovery of the unique catalytic activity of a dimeric palladacycle (Pd2(P(o-Tol)3)(/l-OAc)2) by Herrmann and 12 PR2 Beller has set a milestone in palladium catalysis as it allows the use PR2 of even unreactive chloroaryl substrates in Heck transformations. A variety of chiral phosphine ligands are frequently used for asym­ (R)·BINAP metric Heck reactions. The oxidative insertion is favored by basic ligands whereas bidentate ligands with a small bite angle enable good to excellent chirality transfer (>90 % ee). Some selected ligands which meet these requirements for asymmetric Heck reactions are shown in the margino phosphinooxazoline To account for the differences in reactivity and enantioselectivity observed in Heck reactions of unsaturated triflates and halides, two distinct mechanistic pathways have been proposed (as shown in the (R,R}-OIOP margin). The "cationic" pathway is generally invoked to describe asymmetric Heck reactions of unsaturated triflates or halides in the presence of Ag(I) or TI(I) additives. In the absence of such additives o the Heck reaction is expected to proceed through a "neutral" reaction Pd R 'x pathway. The modest enantioselectivity ofien observed in Heck cationic ~ " neutral pathway pathway reactions of this type has been attributed to the formation of a neutral -'K palladium-aIkene complex by partialligand dissociation.9 Control over regioselectivity in the formation ofthe new C-C a-bond is required to employ the Heck reaction in complex molecule synthe­ [9r siso For intramolecular Heck reactions, regiocontrol in the migratory insertion step is largely govemed by the size of the ring being formed. 11 Poor regioselectivity in the ~-hydride elimination step limits the use of the asymmetric Heck reaction for the construction of tertiary stereo­ [Q]+ R~ centers. The use of cyclic aIkenes as substrates prevents the formation of the undesired double-bond isomer during the ~-hydride elimination j step. However, Tietze and coworkers have demonstrated that this main disadvantage of the Heck reaction can be overcome by using an 0]+ o 13 [R, "Pd R Pd allylsilane as the terminating aIkene component. This procedure ' " X allows the regioselective formation of tertiary stereogenic centers even from acyclic alkenes. An additional concem arises from the reversibility of the ~-hydride Il-hydnde elimination step. The hydridopalladium(I1) species is formed upon elimination L2XHPd"{::)O ~-hydride elimination and there is the possibility that this complex re­ R1 hydro- ¡ adds across the initially generated double bond of the product. palladation H Depending upon the regio- and stereochemistry of this hy­ L2XHP1 ~-hydride XL2Pd,·,CO dropalladation step, subsequent ~-hydride elimination could regener­ C)o elimination ate either the initial Heck product or a regioisomer thereof.9,1O,1l R1 R1
17. 4 1 Minfiensine 1.3 Overview
18. 1 Minjiensine 5
19. 6 1 Mirifiensine 1.4 Synthesis Problem () N H morpholine Hints • Morpholine is a secondary, cyc1ic amine which reacts with alde­ hydes and ketones to give enamines with the formation of water. • The morpholine enamine reacts in an acid-catalyzed transamina­ tion with 2-siloxyaniline 7. Solution TIPSO O elN!:) H 8 Discussion The enantioselective total synthesis of 1 commences with the forma­ tion of the enamine of morpholine and cyc1ohexane-l,2-dione (6), which actually exists almost entirely in the enolic formo Constant removal of water shifts the equilibrium to the side of the product. 2-Siloxyaniline 7,14 which can be easily prepared from 2-aminophe­ nol, reacts with the morpholine enamine15 in an acid-catalyzed trans­ amination to give enamine 8. ::0 7 6
20. 1 Minjiensine 7 Problem • Sodium hexamethyldisilazide (NaHMDS) is a sterically deman­ Hints ding and strong but non-nucleophilic base. • Which is the most acidic proton in 8? • The conditions were carefully adjusted to avoid a competitive reaction ofthe cyclohexenone moiety. • The secondary amine is selectively protected in presence of the cyclohexenone and enamine moieties. TIPSO O Solution Ci)::) I Me02C 9 The sodium salt of enamine 8 is formed by deprotonation with Discussion NaHMDS followed by selective N-protection with methyl chloro­ formate at -78 oC to give carbamate 9 in 52-60 % yield. Problem CI~ t.AN N(Tf)z Comins' reagen! TI: !riHuoro­ me!hylsulfonyl • Comins' reagent is a reagent to introduce triflate moieties. Hints • The triflate of the kinetic enolate is formed.
21. 8 1 Minjiensine Solution 10 Discussion In presence ofNaHMDS the enolate of enone 9 is formed at -78 oC. Reaction of the enolate with Comins' reagent (2-[N,N-bis(trifluoro­ methylsulfonyl)amino ]-5-chloropyridine)16 provides dienyl triflate 10. Problem 9-BBN Hints • 9-BBN (9-borabicyc10[3.3.1]nonane) is a standard reagent for the hydroboration of alkenes. • In hydroboration reactions the boron moiety adds regioselectively to the less-substituted terminus of the alkene. • Under palladium(O) catalysis, a cross-coupling reaction takes place to form a carbon-carbon bond. • The cross-coupling reaction is initiated by oxidative addition of palladium(O) into the carbon-triflate bond. Solution 12
22. 1 Minfiensine 9 The introduction of the aminoethyl side chain is accomplished by Discussion Suzuki cross-coupling of dienyl triflate 10 with the alkyl borane gener­ ated by hydroboration of N-vinyl-tert-butyl carbamate (11) with 9-BBN.17 The Suzuki cross-coupling reaction is an alternative to Stille cross­ coupling, which uses stannanes as metal organic components. One advantage of the Suzuki cross-coupling is the use of nontoxic and easy-to-handle organoboron compounds as coupling partners, which are readily accessible from the corresponding alkenes by hydroboration. This fact facilitates the structural fine tuning of the organometallic reagents. One drawback might be that in general a base (such as KOHaq, K2C03/MeOH, TIOEt) is necessary to activate the system by forming an ate-complex at boron to accelerate the transmetallation step. If a base is liberated in the course of the reaction, no external base is necessary for a successful Suzuki cross­ coupling reaction. A simplified mechanism of this cross-coupling reaction is shown in [Pd(O)L,l R.X. L,Pd(lI(x the margino The mechanism involves oxidative addition of an alkenyl oxidative R or aryl triflate (R-X) to the initial palladium(O) complex to form a R.R' ~ addition ~2:~~BL2 palladium(I1) species. In most cases, the rate-determing step is transmetallation, so called because the nucleophile is transferred from redu:ti~ J,a:s~etallation elimination the metal in the organometallic reagent to the palladium. The new R' L,Pd(lI( palladium(I1) complex with two organic ligands undergoes reductive R elimination to give the cross-coupled product and the palladium(O) catalyst is regenerated for another catalytic cycle.!O·ll Problem • The aryl triflate 13 is forrned in one step from silyl ether 12. Hints • A source of fluoride ions is needed to cleave the silyl ether. • y ou have already come across a triflating reagent in an early step of the synthesis. 1. CsF, CS2C03, Comins' reagent, DMF, r.t., 95 %. Solution
23. 10 1 Minjiensine Discussion Aryl triflate 13 is obtained by reaetion of silyl ether 12 with CsF, CS2C03 and Comins' reagent at room temperature. Under these reae­ CI~ tion eonditions the TIPS-ether is c1eaved to provide the eorresponding tÁN N(Tf), phenolate, whieh undergoes reaetion with Comins' reagent to give 13 Comins' reagent triflate in a one-pot protoeol. Problem ~o Ph2P L; 14 k Pfalfz' ligand 1,2,2,6,6-genta­ methylgiperidine (PMP) Hints • In this reaetion 14 is used as an enantiopure ehiralligand for palla­ dium(O). • Under the reaetion eonditions palladium(O) is formed from Pd(OAe)2 which inserts oxidatively into the C-OTfbond. • The aryl palladium species formed attaeks one ofthe double bonds present in 13. • In this asymmetrie Heck reaetion, a quatemary earbon eenter is formed providing a trieyc1ie dienyl earbamate after reduetive elimination of palladium. • Upon addition of exeess trifluoroaeetie aeid to the erude Heck produet, an iminium ion eyc1ization fumishes the tetraeyc1ie eore ofminfiensine (1) without c1eavage ofthe Boe group. Solution 15 16
24. 1 Minjiensine 11 Initial experiments showed that the asymmetric Heck cyclization of 13 Discussion can be realized with several chiral enantiopure ligands. For this trans­ formation, the Pfaltz' ligand18 14 proved optimal providing the dienyl carbamate 15 in an enantioselectivity of 99 % ee. This Heck cyclization is slow under traditional heating (requiring more than 70 h at 100 oC) but can be accomplished in 30 min with no decrease of enantioselectivity at 170 oC in a microwave reactor. Addition of an excess of trifluoroacetic acid to the crude product fumishes (dihydro­ iminoethano)carbazole 15 in 75 % yield over two steps. The transformation that has come to be known as the Heck reaction is broadly defined as the palladium(O)-mediated coupling of an aryl or vinyl halide or triflate with an alkene. The basic mechanism for the Heck reaction of aryl halides or triflates (as outlined in more detail in the Key Chemistry), involves initial oxidative addition of the chiral palladium(O) catalyst to afford a a-arylpalladium(I1) complex. Coordi­ nation of an alkene and subsequent carbon-carbon bond formation by syn insertion provide a a-alkylpalladium(I1) intermediate, which readily undergoes l3-hydride elimination to release the alkene product. Finally, the hydridopalladium(I1) complex has to be converted into the active palladium(O) catalyst to complete the catalytic cycle. ~~8: a - i syn- ~NJ0 tinsertion I Me02C ~ 13 BOCH~ R, ,N ~ Pd * a) Pd(OAch, 14, PMP, toluene, 170 oC, MW, Q=:ÓH then CF3C02H, CH2CI2 I O oC, 75 % Me02C J3-hyd ride elimination ® H J- HPd(L *)OTf - 16 15 99 % ee
25. 12 1 Minfiensine Upon addition of excess trifluoroacetic acid to the crude Heck pro­ duct, an iminium ion cyclization fumishes the tetracyclic core of min­ fiensine (1) without cleavage ofthe Boc group. In conclusion, the 4aR,9aR enantiomer 16 of the 3,4-dihydro-9a,4a­ (iminoethano )-9H-carbazole interrnediate is directly assembled by the catalytic asymmetric Heck-N-acyliminium ion sequence in 99 % ee and 75 % yield over two steps. Interrnediate 15 can also be isolated and converted to 12 in a separate step. The yield in this case is 74 % over two steps. The absolute configuration was secured by single­ crystal X-ray analysis of a heavy-atom derivative.5 Problem Hints • m-Chloroperoxybenzoic acid (m-CPBA) is a standard reagent for the epoxidation of alkenes. • One of the two protective groups present in 16 is cleaved under acidic conditions. • In the last step of this sequence, the liberated functional group is again protected, but this time with the acid-stable allyloxycarbonyl group (alloc: CH2=CHCH20COR). Solution 17 Discussion In this three-step sequence, alkene 16 is first epoxidized with m-CPBA providing the a-epoxide in 87 % yield along with only minor amounts of the ~-isomer (lO %). As the aminal fragment
26. 1 Mirifiensine 13 present in 16 tends to open under aeidie eonditions/9 the Boe proteetive group has to be exehanged for an ally10xyearbony1 (alloe) group prior to the subsequent synthetie manipulations. Attempts to c1eave the Boe group at the stage of the allylie alcohol led to the fragmentation ofthe six-membered ringo The Boe proteetive group is c1eaved under aeidie eonditions to give the free seeondary amine, whieh is proteeted with the aeid-stable allyloxyearbonyl group (alloe) to yield epoxide 17 in 78 % yield over three steps. Problem • Alkyl phenyl selenoxides bearing a ~-hydrogen undergo syn elimi- Hints nation to form olefins. • Selenium anions are exeellent nuc1eophiles. • The epoxide is opened to give a hydroxyl selenide. • Upon hydrogen peroxide-indueed elimination an allylie alcohol is formed. • The allylie alcohol is proteeted as a silyl ether under basie eonditions. OTES Solution ~: CcQ)N :., I N Me02C Alloc 18 Alkyl phenyl selenoxides bearing a ~-hydrogen undergo faeile syn Discussion elimination to form olefins under mueh milder eonditions than the eorresponding sulfoxides. The selenium anion formed from (PhSe)2 is an exeellent nuc1eophile and easily opens the epoxide to give the eor­ responding hydroxyl selenide. This intermediate is not isolated but
27. 14 1 Minfiensine o direct1y oxidized by excess hydrogen peroxide to provide an unstable ~ \Q~e - ;:c:: selenoxide. The selenoxide readily decomposes to the E allylic alco­ SePh SePh hol. One advantage of this protocol is that the syn elimination occurs excess H20 2 ! "away" from the hydroxyl group. Thus, in most cases, no more than traces ofthe possible carbonyl product are observed.20 allylic alcohol + HOSePh After deprotonation with imidazole, the allylic alcohol is protected as a silyl ether. Problem Hints • Under the reaction conditions of the first transformation, one protective group is c1eaved and, afterwards, a hetero-carbon bond is formed. • Tosyl groups represent very good leaving groups. • In the second step of this sequence, a carbon-carbon bond is formed under palladium(O) catalysis. • In this reaction, palladium(O) inserts oxidatively into the carbon­ iodide bond. • y ou have already come across this type of transformation in the course ofthis total synthesis. Solution 19 Discussion The alloc protective group is c1eaved by palladium providing a secon­ dary amine, which is alkylated by (Z)-2-iodo-2-butenyl tosylate21 to give the corresponding vinyl iodide in 96 % yield. The latter vinyl
28. 1 Minfiensine 15 iodide is converted in a Heck reaction to pentacyc1ic diamine 19 applying conditions introduced by Jeffery22 and using sodium formate as a reductive trap. The mechanism of this intramolecular Heck reaction involves the generation of the active Pd(O) catalyst from Pd(OAc)2. Stereospecific syn insertion into the alkene provides a a-alkylpalladium(II) intermediate. Usually this intermediate would undergo syn /3-hydride elimination to release the alkene product. In this case there are no syn /3-hydrogen atoms with regard to palladium and the conformation of the pentacyc1ic system is fixed, thereby preventing rotation around a C-C bond followed by syn /3-hydride elimination. The use of sodium formate as a reductive trap leads to the release of the palladium from the a-alkylpalladium(II) intermediate with formation of carbon dioxide to give pentacyc1ic diamine 19. oxidative addition 19
29. 16 1 Minjiensine Problem Hints • First, the silyl protective group is cleaved. • Oxidation of the free secondary alcohol provides a ketone. • Enolates are versatile intermediates for functionalization of posi­ tions ato carbonyl groups. Solution 1. TBAF, THF, r.t., 100 %. 2. DMP, CH2Cb, r.t., 99 %. 3. CNC02Me, LiHMDS, THF, -78 oC, 71 %. Discussion Silyl protective groups can be cleaved by fluoride ions. Acidic and basic conditions are also suitable for the cleavage of silyl protecting groups and are commonly used. As a source of fluoride ions, tetrabu­ tylarnmonium fluoride (TBAF) has found widespread application. The secondary alcohol is oxidized to the corresponding ketone with Dess-Martin periodinane in 99 % yield. 1 After formation of the enolate by deprotonation with LiHMDS, the ester moiety is introduced by reaction with methyl cyanoformate to give p-ketoester 20 in 70 % yield over three steps. Structure 20 [6%:.] represents a 1,3-dicarbonyl compound that preferentially exists in the enol formo 1 The use of methyl cyanoformate allows the selective C-acylation of ketones in a regioselective manner to give p-keto ester derivatives. ¿¡oMe This reaction is supposed to proceed via an aldol type intermediate which collapses upon workup to give the p-keto ester.23 Methods based on the use of dialkyl carbonates or dialkyl oxalates do not permit the required control, while reactions with acyl halides or anhydrides usually lead to mixtures of 0- and C-alkylated products. The quenching of lithium enolates by carbon dioxide does provide a general approach to the preparation of a specific regioisomer, but the yields are frequently poor - possibly owing to the formation of unstable enol carbonates, which decompose on workup to retum the starting material.
30. 1 Mirifiensine 17 Problem • This sequence commences with a chemoselective reduction. Hints • The secondary alcohol formed is converted into a good leaving group. • Elimination provides the a,p-unsaturated ester 21. 1. NaBH4, MeOH/THF, O oC, 60 %. Solution 2. BzOTf, pyridine, CHzCh, 60 oC, 100 %. 3. KHMDS, THF, -78 oC, 83 %. The transformation of p-ketoester 20 into a,p-unsaturated ester 21 Discussion requires the reduction of the ketone chemoselectively in the presence of the estero Sodium borohydride (NaBH4) is the standard reagent for this type of transformation. Subsequent reaction of the stericalIy hin­ dered secondary alcohol with benzoyl triflateZ4 provides a good leav­ ing group in P-position to the ester moiety. Elimination under basic conditions provides the a,p-unsaturated ester 21 in 50 % yield over three steps. OH OH Cci:trco,Me _N_aB_H_4__ • Cci:trco'Me N -1 ~ N _1 ~ Me02C N~ MeOi N~ 20 ~ BzOTf OBz ~co'Me KHMDS Cci:trco'Me N _1 ~ Me02C N~ Meoi N~ 21
31. 18 1 Minjiensine Problem Hints • First, the a,p-unsaturated ester 21 is reduced. • As shown in the preceding problem, you need a stronger reducing reagent than NaBl!¡ to reduce an estero • Finally, the carbamate protection group is removed. Solution 1. LiAlH4, 11IF, -20 oC, 89 %. 2. NaOH, MeOHlH20, 100 oC, 95 %. Discussion Reduction ofthe a,p-unsaturated ester 21 with LiAlH4 and subsequent removal of the carbamate protectiongroup provides minfiensine (1) in 85 % yield over two steps. 1.5 Conclusion In this chapter, a concise catalytic asymmetric synthesis entry to al­ kaloids containing the 1,2,3,4-tetrahydro-9a,4a-(iminoethano )-9H­ carbazole (4) ring is presented and the enantioselective total synthesis of minfiensine (1) is discussed in detail. The key step of this synthesis is a sequential asymmetric Heck-N­ acyliminium ion cyclization of dienyl carbamate triflate 13 to provide enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 16. This intermediate and related structures containing a 2,3-double bond should represent versatile precursors for constructing a variety of pentacyclic indole alkaloids containing the (hydroiminoethano )-carba­ zole fragment.
32. 1 Minfiensine 19 1.6 References G. Massiot, P. Thépenier, M. Jacquier, L. Le Men-Olivier, C. Delaude, Heterocycles 1989,29, 1435-1438. 2 For a review, see: U. Anthoni, C. Christophersen, P. H. Nielsen, in Alkaloids: Chemical and Biological Perspectives, (Ed.: S. W. Pelletier), Wiley-VCH, New York, 1999, Vol. 14, pp 163-236. 3 A. 1. Scott, Acc. Chem.Res.1970,3, 151-157. 4 a) A. Ramírez, S. Garcia-Rubío, Curro Med. Chem. 2003, la, 1891-1915; b) V. Saraswathi, V. Mathuram, S. Subramanian, S. Govindasamy, Cancer Biochem. Biophys. 1999, 17, 79-88. 5 A. B. Dounay, L. E. Overman, A. D. Wrobleski, J Am. Chem. Soco 2005,127,10186-10187. 6 a) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soco Jpn. 1971, 44, 581-583; b) R. F. Heck, J. P. Nolley, J Org. Chem. 1972, 37, 2320-2322. 7 N. E. Carpenter, D. J. Kucera, L. E. Overman, J Org. Chem. 1989,54,5846-5848. 8 Y. Sato, M. Sodeoka, M. Shibasaki, J Org. Chem. 1989, 54, 4738-4739. 9 Selected reviews on Heck reactions: a) L. F. Tietze, H. Ha, H. P. Bell, Chem. Rev. 2004,104,3453-3516; b) A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945-2963; e) 1. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009-3066; d) A. de Meijere, F. E. Meyer, Angew. Chem. 1994, 106, 2473-2506; Angew. Chem. lnt. Ed. Engl. 1994,33,2379-2411. 10 J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University Press, Oxford, 2001. 11 A. de Meijere, F. Diederich, Metal-catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, 2004. 12 W. A. Herrmann, C. Brossmer, K. Ofele, C.-P. Reisinger, T. Priermeier, M. Beller, H. Fischer; Angew. Chem. 1995, 107, 1989-1992; Angew. Chem. lnt. Ed. Engl. 1995,34, 1844-1848. 13 a) L. F. Tietze, R. Schimpf, Angew. Chem. 1994, 106, 1138- 1139; Angew. Chem.lnt. Ed. Engl. 1994,33, 1089-1091; b) L. F. Tietze, T. Raschke, Synlett 1995, 597-598; e) L. F. Tietze, T. Raschke, Liebigs Ann. 1996, 1981-1987. 14 Y. Kondo, S. Kojima, T. Sakamoto, J Org. Chem. 1997, 62, 6507-6511. 15 M. Ohashi, T. Takahashi, S. Jnoue, K. Sato, Bull. Chem. Soco Jpn. 1975,48, 1892-1896. 16 D. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299- 6302.
33. 20 1 Minjiensine 17 A. Kamatani, L. E. Overman, J. Org. Chem. 1999, 64, 8743- 8744. 18 O. Loiseleur, P. Meier, A. Pfaltz, Angew. Chem. 1996,108,218- 220; Angew. Chem. Int. Ed. Engl. 1996,35,200-202. 19 H. v. Fritz, O. Fischer, Tetrahedron 1964, 20,1737-1735. 20 K. B. Sharpless, R. F. Lauer, J. Am. Chem. Soco 1973, 95, 2697- 2699. 21 V. H. Rawal, C. Michoud, Tetrahedron Lett. 1991, 32, 1695- 1698. 22 a) T. Jeffery, Tetrahedron Let!. 1985, 26, 2667-2670; b) T. Jeffery, Tetrahedron 1996, 52,10113-10130. 23 a) L. N. Mander, S. P. Sethi, Tetrahedron Lett. 1983, 24, 5425- 5428; b) F. E. Ziegler, T.-F. Wang, Tetrahedron Lett. 1985,26, 2291-2292; e) S. R. Crabtree, W. L. Alex Chu, L. N. Mander, Synlett1990,169-170. 24 L. Brown, M. Koreeda, J. Org. Chem. 1984, 49, 3875-3880.
34. OH O OH O 2 Myriaporone 4 (Taylor 1998, 2004) 2.1 Introduction Myriaporones are a c1ass of natural compounds that were first isolated in 1995 and show antitumor activity against some cancer cell lines.! From their structures it is assumed that they stem from the polyketide ~o OH o OH o biosynthesis pathway. It has been argued that the somewhat unusual 1 exo-methylene group at C-6 in myriaporones 1 (1) and 2 (2) is a result Myriaporone 1 of the isolation process via elimination of an acetate group rather than a part ofthe actual natural product,z' The structure of the highly oxygenated molecule· 4 comprises two primary and two secondary alcohols, two ketone functionalities, an epoxide and a Z-configured double bond. Altogether, seven stereo­ 2 genic centers are present. Similar to carbohydrates such as glucose, Myriaporone 2 the molecule can cyc1ize to form a six-membered hemiacetal that exists in equilibrium with the open-chain formo Nevertheless, both I , , (OH(O~ constitutions of the natural product have been assigned different . names, namely myriaporone 4 (4) and myriaporone 3 (3) for the open­ o OH o OH chain and the cyc1ic isomer, respectively. 3 To date, two total syntheses of myriaporone 4 are known,z This Myriaporone 3 chapter is based on the total synthesis of myriaporone 4 published by Taylor et al. in 2004.2' The synthesis of a chiral precursor, which has also been employed for the total synthesis of related compounds, was published by the same group in 1998.3 The linear total synthesis starts with an enantiomerically pure molecule from the chiral pool that delivers the stereogenic center at C-12 of the final product, employs Evans aldol reactions4 as key steps for stereoselective chain elonga­ 4 tions and additionally inc1udes reductionloxidation steps as well as Myriaporone 4 protecting group chemistry. The authors have inc1uded a stereo-unselective dipolar cyc1oaddition to provide two diastereomers of the final product in order to assign the hitherto unknown stereochemistry at C-5 of the natural producto Therefore, separation of isomers was necessary once in the course of the synthesis to obtain diastereo- and enantiopure myriaporone 4 and its C-5 epimer.
35. 22 2 Myriaporone 4 2.2 Key Chemistry: Evans Aldol Reactions4 Reactions of enolates 5 with aldehydes 6 to form p-hydroxy ketones 7 are called aldol reactions_ Typically, two stereogenic centers are formed in the course of the reaction, thus raising the question of (a) simple syn/anti- and (b) induced stereoselectivity, The syn/anti-ratio in 7 is normally controlled by the enolate double-bond geometry, which is determined by the reaction conditions ofthe enolate-forming step. As a rule, E-configured enolates give the anti isomer while Zimmermann- Trax/er transition state with E-enolale Z-enolale Z-configured enolates give the syn isomer. This rule can be derived from the Zimmerman-Traxler model5, which assumes the cyclic six­ membered transition states 8 or 9 (M = enolate counterion). The term "induced selectivity" addresses the question of the absolute ["t~11~' stereochemistry of the fmal product. To achieve good induced 8 9 selectivity (for any reaction), three conditions need to be fulfilled: ~ ~ X X 1. There must be enantiopure chiral information in the stereoselective R H ' r~~o • r~~o. step. This can be achieved either by using covalent attachment to ~O ~o H R' one of the substrates (stereoselective auxiliary-based methods) or 111 by creating a complex that is cleaved after the stereoselective "O O elementary step under the reaction conditions and reused for the next molecule (stereoselective catalytic methods). Substrate R2VX R' control is observed when the substrates themselves are chiral, anti-7 syn-7 2. The chiral information must be fixed in space to shield one side of the molecule. This can, for example, be achieved by complex formation (e.g. chiralligands on Lewis acids), hydrogen bonding, dipole-dipole interactions or chelation, 3. The chiral information must be close enough to the reacting center or be large enough to effectively prevent attack from one side of the molecule. O O Evans and coworkers have developed chiral oxazolidinone auxiliaries HNAO HNAO such as 10 and 11 that are easily obtainable from (S)-vanilol or from ' J '~ 4a Me"" Ph (IS,2R)-norephedrine. As well as the excellent selectivities obtained ~10 11 in aldol reactions, ease of attachment and removal of these auxiliaries has made this method widely popular. The auxiliary may be recovered and reused after cleavage from the aldol product. ®. ®. The auxiliaries are attached as amides to the carbonyl compound that ec! ''o eó' ''o is to be enolized. Because of chelation of the enolate counterion to the R~ -Z N O rN~ auxiliary carbonyl oxygen, the auxiliary is fixed and prevents R }-J R}-J IR' formation of E-configured enolates 13; only Z-configured enolates 12 12 13 are obtained. Therefore, normally only syn-configured aldol products Z-enolale E-enolale syn-7 are available with this method. The enolate counterion (typically lithium when using LDA as base, or boron derivatives when using a mixture of NEt3 and R2BOTf as
36. 2 Myriaporone 4 23 enolizing agents) is crucial for the outcome of the induced stereo­ selectivity because it determines the way the auxiliary is fixed in the transition state. Lithium ions may accept more than two ligands and thus fix the auxiliary in the transition state 15 by chelation to (1) the enolate oxygen, (2) the aldehyde oxygen and (3) the auxiliary carbonyl group. On the other hand, boron can only accept a maximum of two ligands: The auxiliary position in transition state 17 is fixed by minimization of the overall dipole, which is lowest when the auxiliary carbonyl moiety points away ftom the boron. The aldehyde approaches the enolate ftom its less-hindered face. The chiral center is c10se enough to the reacting center (l,4-induction) and is large enough to almost completely prevent the atiack ftom the other side that would lead to opposite stereochemistry. Note that Xc is used when drawing molecules as an abbreviation to denote the chiral auxiliary. :j: ® O e ,Li, 2Jl OH o o' 'o R H ¡" ("AN o" 6 R~N)( e" .E!l 2 ~H~ }:g_;,LI - R yXc H :::::::-' R1 -(::o - R2 o R1 15 7 chelate :j: R~/R o e ,B, o(¡; o' 'o R2JlH ~N OH o OH OH 6 H R J;;: I ® R2y +H-Xc R~N)( • R2 ,' """O :,B'R R2yXc - R' 10 H'~ , (::o -"'::0e R1 18 R1 17 7 1LiBH 4 minimized dipole OH O R2VXC By changing the counterion it is possible to obtain either one or the R' other isomer of the desired aldol product. 7 There are several ways to cleave the auxiliary ftom the product 7. 1.HN(CH3)(oMe), 1 A1Me3 Typical reactions inc1ude reduction with complex hydrides such as 2.DIBAL LiBIl¡ to obtain the alcohol 18 or transamination to the Weinreb OH O 2) Jl + H-Xc amide and subsequent reduction with DIBAL to give the aldehyde 19 R' I-H that would have been obtained ftom direct aldol reaction.6 R' 10 19
37. 24 2 Myriaporone 4 2.3 Overview
38. 2 Myriaporone 4 25
39. 26 2 Myriaporone 4 2.4 Synthesis Problem Hints • The first step is a protection step; otherwise, product 21 cannot be obtained when applying the subsequent steps. • The next two steps are needed to transform an ester to an aldehyde. Solution 1. PMB trichloroacetimidate, PPTS, CH2Ch, r.t., ovemight, 85 %. 2. LiBH4, Et20, r.t., ovemight, 85 %. 3. TEMPO, NaOCI, KBr, NaHCO}, CH2Ch, 25 min, 93 %. Discussion After protection of the alcohol as p-methoxybenzyl (PMB) ether, the ester functionality is reduced to an alcohol and then reoxidized to the aldehyde 2l. The order of firstly reducing an ester or an acid to the corresponding A~~ alcohol and then reoxidizing it to an aldehyde is quite typical in ~ 11 O. o organic synthesis, as it is often impossible to control the reduction step to stop at the aldehyde stage. There are, however, several possibilities TEMPO R/'-OH 35 34 to selectively oxidize an alcohol to an aldehyde, sorne of which are 3ri presented in this chapter, namely oxidations using TEMP07, IBX and DMP.8 Here, reduction of the ester 20 is accomplished with lithium borohydride LiBH4• Then, selective oxidation fumishes aldehyde 21 in 93 % yield. Tetramethylpiperidine-N-oxyl (33) (TEMPO) is first oxidized with NaOCI to give the N-oxoammonium salt 34. KBr is added to the reaction mixture because the bromide salt of 34 is better soluble in organic solvents than the primarily formed chloride. The ¡R~Ol reaction of alcohol 35 with 34 then affords 36 or 37, depending on the attacked atom. Attack of the lone pair of the nitrogen atom in 36 or the oxygen atom in 37 on one ofthe a-hydrogen atoms ofthe alcohol then ~-A/ \ I eO H OH gives the desired aldehyde 38, and 39 or 40. A 1,2-hydrogen shift 39 40 converts 39 to 40, which is reoxidized to the nitrosium ion 34. Thus, catalytic addition of TEMPO is sufficient while NaOCI must be used in stoichiometric amounts.
40. 2 Myriaporone 4 27 Problem • A nuc1eophile adds to the most electrophilic position in 21. Hints 1. t-BuLi, 2-bromopropene, THF, -78 oC, 20 min, then 21, -78 oC, Solution 20 min, 91 %. A halogen-lithiurn exchange in the reaction of t-BuLi and 2-bromo­ Discussion propene (41) affords 2-lithiopropene (42) which then adds to the carbonyl double bond. After aqueous workup, alcohol 22 is obtained as a mixture of isomers. Powerful C-nuc1eophiles are available from metal-halogen exchange reactions. While halogenated compounds are electrophilic (because of the higher electronegativity of the halo gen compared to carbon), metallated compounds act as nuc1eophiles. Because of steric bulk, t-BuLi does not react as a nuc1eophile in an Swreaction with bromide 41 but affords exc1usively the lithiated intermediate 42. 1. SOCi;, CH2C1;~, Problem "'::7$. oC, 6 h 2. CsOAc,DMF,40 .~C, 6.h: 50% (2 steps) PM~Q~ , " ~ , 23 ··.OH·· 3 1<2(;03, MepH, r.t., 22. 2 h,.90% • Product 23 has only one stereogenic center. Hints • In the first step, a chlorine atom is introduced while the hydroxy group leaves the molecule. • There is no more chlorine left in the product. • How do a base and an alcohol donor act on an ester?
41. 28 2 A1yriaporone 4 So/ution PMBO~ OH 23 Discussion The reaction ofthionyl chloride SOCb (43) with the secondary allylic alcohol 22 first gives chlorosulfite 45, which is not stable but eliminates S02 with formation ofthe rearranged primary allyl chloride 47 (path a) or of a secondary chloride 49 (path b).9 Such reactions are termed "SNi"-reactions, for "intemal" substitution reactions. Since the cyclic six-membered transition state 46 for path a is lower in energy, 47 is selectively formed at -78 oC. From the transition state it can be seen why only the E-configured product is obtained. When this reaction is performed at a higher temperature, side product 49 is formed in isolable amounts. :j: :j: PMBO~ PMBO~ o~ 01 onel S S 11 11 46 O 48 O !a !b PMBO~ PMBO~ el el 47 49 The following two steps are used to transform the primary allylic chloride 47 into the corresponding primary allylic alcohol 23. Nucleophilic substitution of the chloride with CsOAc gives an acetate which is then saponified under basic conditions to form alcohol 23 and methyl acetate.
42. 2 Myriaporone 4 29 Problem • The second step is an Evans aldol reaction. Hints • How can 23 be transfonned into a substrate for an aldol reaction? • What is the substrate that contains the Evans auxiliary? 1. IBX, DMSO, r.t., 30 min, 95 %. Solution 2. 50, CH2Clz, BU2BOTf, NEt3, -78 oC, 50 min, O oC, 10 min, then the aldehyde, -78 oC to -20 oC, 2 h, -15 oC, 1 h, 93 %. 50 Product 24 contains a secondary alcohol at the position where the Discussion primary alcohol was in substrate 23. Prom that it can be seen that 23 is frrst converted into the corresponding aldehyde, which then acts as electrophile in the following aldol reaction. Here, oxidation to the aldehyde is perfonned with the iodo(V)-reagent IBX (o-iodoxy­ benzoic acid, 51).8 After addition-elimination, species 52 is fonned, which disproportionates to the iodo(IlI)-compound 53 and the desired aldehyde 38. H H ) ('{-R OH R'/"OH f 35 c($H 0 I O I O I O .ó - H20 .ó O ~.ó O d7O -RAH O 51 52 53 IBX 38
43. 30 2 Myriaporone 4 e The following Evans aldol reaction employs the enolate 54 of an u,f)­ o unsaturated system 50.4c Such enolates may attack in the u- or y­ ~Xc position to an electrophile. However, because of the energetically accessible cyclic six-membered Zimmerman-Traxler transition state5 o NEt3 o in comparison to a possible cyclic eight-membered transition state, ~- only product 24 is formed. "'" Xc - HNEt3 ~Xce 50 The syn product is obtained because of the enolate's Z-configured I o double bond. The induced stereochemistry can be explained by the Y~ competing Zimmerman-Traxler transition states 55-58. e Xc 54 :j: :j: OlJ"'lf"pN I r iPr~1o fJ!:ó~ fJ!:ó~ 55 24 56 steric bias minimized steric bias maximized dipole minimized dipole maximized :j: 57 59 58 steric bias maximized steric bias minimized dipole minimized dipole maximized Minimum steric interactions between the auxiliary's isopropyl group and the aldehyde and optimal dipole minimization make transition state 55 the lowest in energy. All other possible combinations lead to transition states of significantly higher energy. This explains the excellent observed stereoselectivity. Problem 2,6-lutidine
44. 2 Myriaporone 4 31 • The reagents TBSOTf and TBSCl are used for the protection of Hints alcohols. TBSO Solution PMBO~ OTBS 25 A base and a silyl halogenide (e.g. TBSCI) or triflate (e.g. TBSOTt) Discussion are cornrnon reagents for the protection of alcohols. The deprotonated alcohol reacts in an SN reaction with the silyl species. In contrast to TBSCI, TBSOTf is reactive enough to also react with secondary hydroxy groups. After protection of the secondary alcohol with TBSOTf, the Evans auxiliary is cleaved under reductive conditions with LiBlL¡ to afford the prirnary alcohol, which is afterwards protected with TBSCI to form25. Problem • Which functional group in 25 is attacked by OS04? Hints • The product of the second step is an aldehyde that contains one carbon atom fewer then the substrate. • The third step is an Evans aldol reaction and employs the enolate of 26 that is the enantiorner of 50 that was used in the previous aldol reaction. The stereochernistry of the reaction is entirely reagent-controlled. Can you draw the favored transition state and predict the stereochemical outcome ofthe reaction?
45. 32 2 .Myriaporone 4 Solution )/1"'("'0 TBSO O N-" - Y ~ = = O PMBO ~: Ó : TBS6 OH I 27 Discussion Osmium tetroxide is a reagent that transforms double bonds to 1,2- diols. For steric reasons, only the terminal double bond of 25 is OsO. H20 R~OH R~ '. l attacked. OS04 is an expensive and very toxic reagent; therefore, it is - Os02(OH), OH used in catalytic amounts in the presence of N-methylmorpholine N­ 60 61 oxide (NMO, 62), which reoxidizes the Os(VI)-species Os02(OR)2 to the Os(VIII)-species OS04. When performing the reaction in this catalytic fashion, water must be present in the reaction mixture to quench the primarily formed osmate ester to afford the diol 61 and the 62 63 Os(VI)-species. NMO Periodate ions 104- react with 1,2-diols to form periodate esters 64 that are unstable and release iodate ions 103-, During that process, the R~OH 10~ R v<> carbon bond is oxidatively c1eaved and two aldehydes result. Rere, the 5 - 5' ""0 OH 01 ,/ desired aldehyde 66 and formaldehyde (65) are formed. 61 ~I~O O OH The last reaction of this sequence is another Evans aldol reaction / 64 employing the enantiomer ofthe a,~-unsaturated ketone that was used R'y'H + H'y'H 8 before. From the stereochemical outcome of the reaction it can be seen 11 11 + 103 O O that the existing stereogenic centers do not influence the induced 66 65 selectivity. 27 is formed exc1usively as one enantiopure diastereomer via transition state 67. :j: 67
46. 2 Myriaporone 4 33 Problem • What reagent cleaves the Evans auxiliary? Hints • How is the primary alcohol selectively protected in the presence of a secondary aleohol? 1. LiBR¡, Et20, H20, O oC, 1 h, r.t., 1 h. Solution 2. NEt3, TBSCI, DMAP, CH2Ch, r.t., ovemight, 97 % (2 steps). After reductive cleavage of the Evans auxiliary, the resulting aleohol Discussion is TBS-protected employing TBSCl. This reagent is not reactive enough to react with secondary aleohols and thus selectively protects only the primary aleohol. Problem • The reaction of n-PrN02 and PhNCO affords a nitrile oxide that is Hints a 1,3-dipole. • Where is there a dipolarophile in the substrate?
47. 34 2 Myriaporone 4 Solution T880 /OT88 PM80 .ó 5 :: / T880 OH O-N 5R: 29a 5S: 29b Discussion A 1,3-dipolar cycloaddition is a pericyclic addition in which a 1,3- dipole reacts with a dipolarophile to form a five-membered ringo ~N02 Common dipolarophiles are alkenes and alkynes. Since 1,3-dipoles 68 typically contain heteroatoms, these reactions are often used to PhNCO produce five-membered heterocycIes. - PhNH2 From the parent nitro compound n-PrN02 (68), formal elimination of -C02 one water molecule with phenyl isocyanate gives the desired nitrile oxide 69 (the 1,3-dipole), aniline and CO2• Then, an isoxazoline is - 8 [8,~~O O' N~l made by cycIoaddition of 69 with the terminal olefin of the substrate (dipolarophile ).10 69 R~ O-N 71 Isoxazolines are used in organic synthesis because they mask a number of functionalities such as f3-hydroxyketones or y- or f3-amino alcohols. While they are not affected by the reaction conditions of many organic transformations, they can be easily unmasked in later steps of the synthesis.ll In fact, because of its wide applicability, this cycIoaddition-reductive opening procedure has been termed the "isoxazoline route" .12 As mentioned before, this cycIoaddition is deliberately stereo­ unselective so as to produce two diastereomers of myriaporone 4, in order to assign the hitherto unknown stereochemistry of the natural product at C-5. However, it was not possible to separate 29a and 29b at this stage. Therefore, total synthesis was continued with the mixture of isomers before separating them via column chromatography after three additional steps.
48. 2 Afyriaporone 4 35 Problem • DDQ is used to deprotect PMB-protected alcohols. Hints • IBX has been used in this total synthesis before. • In the third step, the phosphonium saIt and n-BuLi fonn a Wittig salt in situ. In the subsequent reaction, Ph3P=O is obtained as one ofthe products. Solution T880 OH 30 The left part of the target molecule has now been made: After Discussion deprotection of the PMB-protected alcohol with DDQ (72), the o primary alcohol is oxidized to the aldehyde with the IBX reagent. Then, a Wittig reaction13 with Ph3P=CHCH3 fonned in situ transfonns N"'»CII I ~ the carbonyl compound into a Z-configured aIkene. At this stage, N o CI separation ofthe C-5-isomers is possible to obtain diastereopure 30. 72 DDQ
49. 36 2 Myriaporone 4 Problem Hints • The first step is an oxidation. • To produce a molecule that formally comes from selective deprotection of a secondary TBS ether, two steps are needed. Solution 1. Dess-Martin-periodane (DMP), NaHC03, CH2CI2, r.t., 7 h, 98 %. 2. HF'NEt3, THF, r.t., 5 d, 83 %. 3. TBSCl, NEt3, DMAP, CH2CI2, r.t., ovemight, 81 %. Discussion Dess-Martin-periodinane (DMP,73) is an oxidizing agent that oxidizes the alcohol at C-7 to the corresponding ketone. 8 The A O OAc c '[_OAc mechanism of this transformation is similar to that of the IBX cqI 'o ~ oxidation shown earlier. o There is no simple way to selectively deprotect secondary TBS ethers 73 DMP in the presence of primary TBS ethers. The solution here is a strategy in which all TBS groups are first cleaved and then the primary alcohol groups are selectively reprotected with TBSCl. Common reagents for deprotection of silyl protection groups are fluoride sources such as CsF, TBAF or, as here, hydrogen fluoride in solution in NEt3• Problem
50. 2 Myriaporone 4 37 • Molybdenum hexacarbonyl MO(CO)6 reductively c1eaves N-O Hints bonds in isoxazolines. The reaction of the intermediate with water re1eases ammonia. • Alkenes with hydroxy groups in an allylic position are much more rapidly epoxidized than isolated double bonds. • The stereoselectivity of the epoxidation is substrate-controlled. Solution o OH O 32 In the first step, the isoxazoline N-O bond is reductively c1eaved with Discussion MO(CO)6 in the presence of water to unmask the ~-hydroxyketone 78. 14 First, the nitrogen forms a dative bond to the molybdenum species with its lone pairo This step substantially weakens the N-O bond in 75 and leads to an equilibrium with the nitrene-complex 76. 74 Mo(CO)a Protonation-reduction with water affords ~-imino alcohol 77 which is ! not stable and is further hydrolyzed to the desired ~-hydroxyketone R (i(R_RYl(R 78. The byproduct [Mo(CO)S]2+ can once again reduce an isoxazoline 0-1 - e O le molecule; thus, employing 0.5 equivalents ofthis agent is sufficient to (OC)aMo (OC)aMo complete the reaction. Although hydrogenolysis usually gives higher 75 76 yields for this reaction, it is not applicable because of the double !H 20 bonds present in the molecule. H20 RyyR In the following epoxidation step, meta-chlorobenzoic acid (m-CPBA) ¡- NH3 OH NH has the choice to attack the 10,11-double bond or the 13,14-double 77 bond. Because a hydrogen bond between the alcohol at C-9 and the peracid stabilizes the transition state 80, only the 10,11-double bond is epoxidized. In addition, this hydrogen bond also directs the atlack to come from the same side as the alcohol and thus leads to a high substrate-controlled stereoselectivity. m-CPBA 79 81 80
51. 38 2 Myriaporone 4 Problem Hints • Which ion should the reagent contain to cleave silyl ethers? Solution 1. TAS-F, DMF, 45 min, 70 %. Discussion Total deprotection with tris(dimethylamino)sulfonium difluoro­ trimethylsilicate 15 (TAS-F, (Me2N)3S+F2SiMe3-) afforded the target molecule 4 in 70 % yield. This mild deprotection method is especially useful when dealing with base- or acid-sensitive compounds. 2.5 Conclusion The linear synthesis of the title compound started from an enantiopure building block with one stereogenic center. The other six stereogenic centers were introduced by two reagent-controlled Evans aldol reactions, an unselective 1,3-dipolar cycloaddition with subsequent separation ofthe diastereomers, and a substrate-controlled epoxidation step. The synthesis of myriaporone 4 and its e-5 epimer was achieved in 27 steps in a total yield of 0.91 %. The absolute stereochemistry of the natural product could be elucidated by comparison of its NMR spectrum with those of both synthesized isomers.
52. 2 Myriaporone 4 39 2.6 References K. L. Rinehart, K. Taehibana, J. Nat. Prod. 1995, 58, 344-358. 2 a) K. N. Fleming, R. E. Taylor, Angew. Chem. 2004, 116, 1760- 1762; Angew. Chem. Int. Ed. 2004,43,1728-1730; b) M. Pérez, C. del Pozo, F. Reyes, A, Rodríguez, A. Franeeseh, A. M. Eehavarren, C. Cuevas, Angew. Chem. 2004, 116, 1756-1759; Angew. Chem. Int. Ed. 2004,43,1724-1728. 3 a) R. E. Taylor, J. P. Ciavarri, B. R. Hearn, Tetrahedron Lett. 1998, 9361-9364; b) J. P. Ciavarri, Ph.D. thesis (University of Notre Dame, Indiana), 2001. 4 a) D. A. Evans, J. Bartroli, T. L. Smith, J. Am. Chem. Soco 1981, 103,2127-2129; b) D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soco 1982,104, 1737-1739; e) D. A. Evans, E. B. Sjogren, J. Bartroli, R. L. Dow, Tetrahedron Lett. 1986, 27, 4957 4960. 5 H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soco 1957, 79, 1920-1923. 6 S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815- 3818. 7 For a review, see: W. Adam, C. R. Saha-M611er, P. A. Ganeshpure, Chem. Rev. 2001, 101, 3499-3548. 8 For a review on the oxidation of alcohols with hypervalent iodine reagents sueh as mx and DMP, see: H. Tohma, Y. Kita, Adv. Synth. Catal. 2004, 346, 111-124. 9 a) F. F. Caserio, G. E. Dennis, R. H. DeWolfe, W. G. Young, J. Am. Chem. Soco 1955, 77, 4182 4183; b) W. S. Johnson, T.-T. Li, C. A. Harbert, W. R. Bartlett, T. R. Herrin, B. Staskun, D. H. Rieh,J. Am. Chem. Soco 1970,92,4461 4463. 10 For a review, see: K. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998,98,863-910. 11 For a review, see: P. G. Baraldi, A. Barco, S. Benetti, G. P. Pollini, D. Simoni, Synthesis 1987, 857-869. 12 a) V. Jager, H. Grund, V. Buss, W. Sehwab, 1. Müller, R. Sehohe, R. Franz, R. Ehrler, Bull. Soco Chim. Belg. 1983, 92, 1039-1054; b) A. P. Kozikowski, Acc. Chem. Res. 1984, 17, 410 416. 13 For a review, see: B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989,89,863-927. 14 P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini, D. Simoni, Synthesis 1987, 276-278. 15 K. A. Seheidt, H. Chen, B. C. Follows, S. R. Chemler, D. S. Coffey, W. R. Roush, J. Org. Chem. 1998,63,6436-6437.
53. OH HO 3 Ningalin D (Boger 2005) HO OH OH 1 3.1 Introduction HOM~HH~~OH The alkaloids ningalin A-D were first isolated in 1997 by Fenical and Kang from the marine ascidian of the genus Didemnum sp. collected o ¡, ~ o 1 N in westem Australia near Ningaloo Reef. By far the most complex of o H o these four alkaloids is ningalin D (1) incorporating a biphenylene qui­ 2 none methide superimposed on an oxidized pentasubstituted pyrrole Ningalin A core that characterizes this class of natural products. In the course of developing total syntheses of the simpler members of Ho¿H HbOH the ningalin family, Boger et al. disclosed several derivatives that possess potent P-glycoprotein inhibitory activity, effective multidrug -W resistance (MDR) reversal properties in cellular functional assays, and show efficacious in vivo antitumor activity against sensitive and ~o resistant tumors upon coadministration with antitumor therapeutics (vinblastin, taxol®) in xenograph animal models.2 Although these YOH derivatives lack intrinsic cytotoxic activity themselves, they OH 3 resensitize MDR tumors and hypersensitize sensitive tumors to Ningalin B conventional therapeutics through inhibition of the overexpressed or OH HO constitutive drug efflux pump P-glycoprotein (p_gp).2 P-gp is a 170- HO kDa plasma membrane glycoprotein encoded in humans by the MDRI gene, which exports drugs out of marnmalian cells, lowering their intracellular concentration.3 This chapter is based on the first total synthesis of ningalin D (1) by OH Boger and coworkers, which was published in 2005.4 O~N ~ ~ r' I OH "" OH OH 4 Ningalin e
54. 42 3 NingalinD 3.2 Key Chemistry: Pyrrole Synthesis using a 1,2,4,5-Tetrazine ~ 1,2-Diazine ~ Pyrrole Strategy Key elements of the total synthesis of ningalin D (1) developed by Boger et al. inc1ude an inverse electron-demand Diels-Alder reaction (1,2,4,5-tetrazine + 1,2-diazine) followed by a reductive ring contrac­ tion ofthe resultant 1,2-diazine, affording the fully substituted pyrrole core central to the structure of1. Ar == Ar8 Ar Ar Ar Ar + -W Red_ . "'H" [4+2] N-N ROzC.J(N)\ COzR ===> ROzC {=rCOzR ===> ROZC-\FJCOzR H 5 6 7 The thermal [4+2] Diels-Alder cyc1oaddition reaction can be c1assified into three processes: the normal Diels-Alder reaction of electron-rich dienes with electron-deficient dienophiles (HOMOdiene­ controlled), the neutral Diels-Alder reaction and the inverse electron­ demand Diels-Alder reaction of electron-deficient dienes with electron-rich dienophiles (LUMOdiene-controlled). Heteroaromatic systems that possess an electron-deficient azadiene are ideally suited for participation in inverse electron-demand Diels-Alder reactions.5 Additional substitution of the heterocyclic azadiene system with electron-withdrawing groups accents the electron-deficient nature of the heterodiene and permits the use of electron-rich, strained or even simple olefins as dienophiles.
55. 3 NingalinD 43 Thus, the electron-deficient 1,2,4,5-tetrazine 7 reacts smoothly with the electron-rich acetylene 8 in an inverse electron-demand Diels­ Alder reaction: First, the [4+2] cycloaddition of 7 with 8 takes place and then the formed intermediate 9 loses N2 to provide the symmetri­ cal 1,2-diazine 6. Ar N~Nca,R [4+2] r A N'-k:N C02 R1 A,~~R N 11 1I 1 + N"111 N Ar 4'/ // -N 2 I N Ar "" N Ar 2 C02 R R0 C C02R 8 7 9 6 Such 1,2-diazines can be transformed to the corresponding substituted pyrroles in a reductive ring contraction employing zinc in either acetic acid or trifluoroacetic acid.6 This reductive ring-contraction reaction presumably proceeds via the reduction of 1,2-diazine 6 to the corresponding l ,4-dihydro-l ,2-diazine 10, which is subsequently re­ duced to intermediate 11. Then, 11 undergoes an intramolecular cycli­ zation providing the tetrasubstituted pyrrole 5. 4 Ar Ar Ar Ar Zn/TFA R02CXC02 R R02CXC02 R N=N HN-N 6 10 1 ZnlTFA Ar Ar Ar Ar - NH3 Jr-{ R02CXC02R R02C N C02 R H2N NH H 5 11
56. 44 3 NingalinD 3.3 Overview
57. 3 NingalinD 45
58. 46 3 Ningalin D 3.4 Synthesis Problem Hints • Nitriles can be hydrolyzed in the same way as primary amides. • Addition of methanol to the protonated nitrile gives the correspon­ ding acetimidic acid methyl estero Solution l. H2S04, MeOH, reflux, overnight, 90 %. Discussion The preparation of ester 13 is performed by an acid-mediated hydro­ lysis of nitrile 12 in methanol. The conditions used are quite vigorous: H2S04, El) MeOH "NH2 e concentrated sulfuric acid, re flux (65 oC), overnight. However, in this R-C=N - R-<¡; HS04 OMe reaction the addition of methanol to the protonated nitrile gives the corresponding acetimidic acid methyl ester, and subsequent hydrolysis NH S04 H20 4 -1 of this intermediate provides the desired ester 13 in 90 % yield. R_é"° I OMe Problem Hints • A transition metal-catalyzed cross-coupling reaction is employed. • The alkyne building block is 1,2-bis(tributylstannyl)acetylene.
59. 3 NingalinD 47 1. Pd(PPh3)4 (5 mol-%), 23, toluene, 110 oC, 6 h, 71 %. So/ution (n-BuhSn === Sn(n-Buh 23 The preparation of the symmetrical alkyne 14 is accomplished by a Discussion double Stille coupling of two molecules of aryl bromide 13 with 1,2- bis(tributylstannyl)acetylene (23) in the presence of catalytic amounts ~yPdO\Ar-x of Pd(PPh3)4. 7 The mechanism ofthe Stille reaction involves an oxidative addition of R-~d" X-~d" the palladium(O) species into the carbon-halogen bond, a trans­ Ar Ar metallation reaction with the organostannane and a final reductive eli­ ~ mination step releasing the product and thereby regenerating the palla­ X·Sn(n·Bu), R-Sn(n-Bu), dium(O) catalyst. Problem • What kind of pericyclic reaction could happen under these reaction Hints conditions? • Alkyne 14 is an electron-rich dienophile. • During the reaction the formation ofN2 is observed. MeO MeO OMe OMe So/ution 16
60. 48 3 NingalinD Discussion The electron-rich alkyne 14 reacts with the electron-deficient 1,2,4,5- tetrazine 15 in a thermal inverse electron-demand azadiene Diels-­ Alder cycloaddition reaction (see Key Chemistry). First, the [4+2] cycloaddition of alkyne 14 with tetrazine 15 takes place and then the formed intermediate 24 loses N2 to provide the symmetricall,2-diazine 16. Problem Hints • Pyrrole formation occurs under reductive conditions. • First, the 1,2-diazine is reduced to the 1,4-dihydro-l ,2-diazine. • Then, the N N bond is cleaved. Solution l. Zn, TFA, 25 oC, 7 h, 64 %. Discussion The synthesis of pyrrole 17 is performed by a reductive ring-contrac­ tion reaction effected by treatment of 1,2-diazine 16 with ZnlTFA. Ar'>,-/" 10 First, the 1,2-diazine 16 is reduced to the corresponding 1,4-dihydro- R02C f }-C02 R HN-N 1,2-diazine 10, which is subsequentIy reduced to 11. Then, 11 under­ goes an intramolecular cyclization providing the tetrasubstituted A'\-__t' 11 pyrrole 17 (see Key Chemistry). R02C f ,) C02R H2N NH
61. 3 NingalinD 49 Problem • This step is an N-alkylation. Hints 1. 25, CS2C03, DMF, 60 oC, 2 h, 92 %. Solution I / MeoJ? OMe 25 Pyrrole is much more acidic than comparable saturated amines and Discussion can be converted easily to the corresponding anion. In this synthesis, the cesium carbonate produces equilibrating amounts of the anion of 17 which then reacts with iodide 25 to give product 18.
62. 50 3 NingalinD Problem Hints • An ester enolate is formed. • How can this enolate further react? Solution Discussion The aryl e and D rings are introduced via a double Dieckmann con­ densation,8 which is effected by treatment of18 with NaH. M~eo~;Me 26 First, the ester enolate 26 is formed, which then attacks the aryl ester MeO ;,;. moiety with formation of a six-membered ringo The product under the reaction conditions is the stable enolate 27 but acidic workup forms Na® eO O '/ N \ 1- MeO R phenol19 as the final product. Notably, the second of the two Dieckmann condensations proceeds more slowly than the first. This is because it requires the adoption of a sterically demanding coplanar arrangement ofthe A and B aryl rings.
63. 3 NingalinD 51 Problem • This step is an esterification. Hints Solution R-OTf ~ o R-O-W-" CF3 Me02C o 20 The conversion of bisphenol 19 to the corresponding bistriflate 20 is Discussion perfonned by treating 19 with trifluoromethanesulfonic anhydride (Tf20) in the presence of pyridine.
64. 52 3 NingalinD Problem Hints • The first step is a palladium-catalyzed cross-coupling. • Which organometallic reagent is needed for this transformation? • In the second step the methyl esters are hydrolyzed.
65. 3 NingalinD 53 1. 28 (2.2 eq.), Pd(PPh3)4 (lO mol-%), LiCI (2.2 eq.), 1 M K2C03, Solution DME, 80 oC, 15 h, 88 %. 2. t-BuOK, H20, DMSO, 80 oC, 24 h, 84 %. MeO~B(OHb MeO~ 28 In the first step, bistriflate 20 is coupled with two molecules of 3,4-di­ Discussion methoxyphenylboronic acid (28) employing a double Suzuki cross­ coupling reaction.9 The mechanism of the Suzuki coupling is very similar to that of the Stille coupling that has already been discussed in this chapter. Thus, oxidative addition of the aromatic triflate to the palladium(O) species generates a palladium(I1) intermediate, which then undergoes a transmetallation with aryl boronic acid 28. The final reductive elimination step releases the product and thereby regenerates the palladium(O) catalyst. The important feature ofthe Suzuki coupling is the need for an additional base, which accelerates the trans­ metallation step presumably via the more nucleophilic "ate" complex 29. Interestingly, the inclusion of LiCI in the reaction mixture was crucial for very high yields in this transformation, which in its absence 9T1 LiCI 91 Ar-PdL, ~ Ar-PdL, 10 proved much less effective. This might be due to an exchange of the 30 31 triflate substituent in palladium(I1) species 30 against a chloride sub­ stituent, resulting in a higher transmetallation rateo In the second step, the two methyl ester moieties are hydrolyzed under basic conditions to the corresponding carboxylic acids. Whereas typical saponification methods (2 N KOH, re flux, 48 h) failed, the hydrolysis proceeded smoothly with "anhydrous hydroxide".ll This reagent - relatively unsolvated hydroxide - was generated via the reaction of two equivalents of potassium tert-butoxide with one equi­ valent ofwater.
66. 54 3 NingalinD Problem DPPA= o (PhOlzP-N3 Hints • The carboxylic acid moieties are converted to the corresponding isocyanates in the first step. • Hydrolysis of an isocyanate gives an amine. • In the second step an oxidation of the diamine to the biphenylene quinodiimide and subsequent imine hydrolysis occur. Solution 22 Discussion In the first transformation, the carboxylic acid moieties are converted to the corresponding isocyanates employing a Curtius rearrange­ ment. 12 This transformation starts with the formation of mixed anhy­ dride 33 which is subsequently attacked by the azide anion to give acyl azide 34. Then, acyl azide 34 rearranges with the formation of isocyanate 35 and nitrogen. As isocyanate 35 is unstable to hydrolysis
67. 3 NingalinD 55 it is attacked on the carbonyl group by water to give carbamic acid 36 which decomposes to amine 37. ~O,t(OPh¡' ~~ 33 N~ O El 11 ! - O-P(OPhh In the second step diamine 38 is heated in a mixture of THF and water under an air atmosphere. In this way, the oxidation of diamine 38 to the biphenylene quinodiimide 39 occurs and this is subsequently hydrolyzed to provide permethyl ningalin D 22. DPPA, í-Pr2NEt 21 22
68. 56 3 NingalinD Problem Hints • Phenol methyl ethers are usuaHy cleaved with Lewis acids. Solution 1. BBr3, CH2C12, -78 oC to 25 oC, 16 h, 96 %. Discussion The removal of aH methyl ethers in 22 is performed by using the Lewis acid BBr3' This trivalent boron compound is very electrophilic and attacks the oxygen atom in aryl methyl ether 40 to give intermediate 41. Then, the resulting oxonium ion 42 is attacked by Br­ in an SN2 reaction providing the free phenol 44 after aqueous workup.13
69. 3 NingalinD 57 Br Br, I Br BeI ~OMe BBr3 » (Y~'Me y~ 40 V~ 41 R R !- MeBr 3.5 Conclusion The biologically interesting marine natural product ningalin D (1) was synthesized in 12 steps with an overall yield of 12 %. The key to this total synthesis is a 1,2,4,5-tetrazine + 1,2-diazine + pyrrole Diels­ Aláer strategy to assemble a fully substituted pyrrole core central to the structure of ningalin D (1). In addition, a double Dieckmann condensation to introduce the C and D aryl rings, an effective Suzuki coupling for the introduction of the sterically demanding F and G aryl rings and a formal oxidative decarboxylation reaction cascade initiated by a Curtius rearrangement to directly provide the biphenylene quinone methide were employed. 3.6 References H. Kang, W. Fenical, J. Org. Chem. 1997, 62,3254-3262. 2 a) D. L. Boger, C. W. Boyce, M. A. Labrolli, C. A. Sehon, Q. Jin, J. Am. Chem. Soco 1999,121,54-62; b) D. L. Boger, D. R. Soenen, C. W. Boyce, M. P. Hedrick, Q. Jin, J. Org. Chem. 2000,65,2479-2483; c) D. R. Soenen, 1. Hwang, M. P. Hedrick, D. L. Boger, Bioorg. Meá. Chem. Lett. 2003,13, 1777-1781; d) H. Tao, 1. Hwang, D. L. Boger, Bioorg. Meá. Chem. Lett. 2004, 14, 5979-5981; e) T.-C. Chou, y. Guan, D. R. Soenen, S. J.
70. 58 3 NingalinD Danishefsky, D. L. Boger, Cancer Chemother. Pharmacol. 2005, 56, 379-390. 3 a) N. H. Pate1, M. L. Rothenberg, Invest. New Drugs 1994, 12, 1-13; b) M. M. Gottesman, 1. Pastan, Annu. Rev. Biochem. 1993, 62,385 427. 4 A. Hamasakí, J. M. Zimpleman, 1. Hwang, D. L. Boger, J. Am. Chem. Soco 2005,127, 10767-10770. 5 D. L. Boger, Chem. Rev. 1986,86,781-793. 6 a) N. J. Bach, E. C. Kornfeld, N. D. Jones, M. O. Chaney, D. E. Dorman, J. W. Paschall, J. A. Clemens, E. B. Smalstig, J. Med. Chem. 1980,23,481 491; b) D. L. Boger, R. S. Coleman, J. S. Panek, D. Yohannes, J. Org. Chem. 1984,49,4405 4409; e) D. L. Boger, M. Patel, J. Org. Chem. 1988,53, 1405-1415. 7 a) J. K. Stille, Angew. Chem. 1986,98,504-519; Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524; b) P. Espinet, A. M. Echavarren, Angew. Chem. 2004, 116, 4808 4839; Angew. Chem. Int. Ed. 2004, 43, 4704 4734. 8 J. P. Schaefer, J. J. Bloomfield, Org. React. 1967,15,1-203. 9 N. Miyaura, A. Suzuki, Chem. Rev. 1995,95,2457-2483. 10 A. Huth, 1. Beetz, 1. Schumann, Tetrahedron 1989, 45, 6679- 6682. 11 a) F. C. Chang, N. F. Wood, Tetrahedron Lett. 1964,2969-2973; b) P. G. Gassman, W. N. Schenk, J. Org. Chem. 1977,42,918- 920. 12 P. A. S. Smith, Org. React. 1946,3, 337 449. 13 J. P. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University Press, Oxford, 2001, p. 434.
71. 4 BIRT-377 (Barbas 2005) 4.1 Introduction BIRT-377 (1), a small molecule inhibitor of lymphocyte function­ associated antigen 1 (LFA-l), was frrst discovered by Kelly and coworkers in 1999. 1 It was shown to have potential therapeutic utility in the treatment of a variety of inflammatory and immune disorders. In binding to intercellular adhesion molecules, the cell-surface receptor LFA-l allows many cell-cell adhesion events that control immunological functions. A lack of these synaptic functions leads to potentially life-threatening immunodeficiency diseases. In case of overactive immune responses, an LFA-l inhibitor can be used to attenuate the inflammatory responses.2 These immunosuppressive activities have been tested in vitro, and early c1inical trials on transplantation have already been undertaken.3 The structure of BIRT-377 (1) contains an N-aryl-substituted hydantoin moiety that bears a quatemary stereogenic center at e-5. As the first nonpeptidic antagonist of the intercellular adhesion molecules' binding with the leucointegrins such as LFA-l,z BIRT-377 (1) became an interesting target molecule for total synthesis. The synthesis requires the stereoselective generation of the quatemary center as an altemative to non-catalytic chiral pool approaches such as Seebach's strategy of self-regeneration of stereocenters that was used by Yee in 2000.4 Known methods for the synthesis of quatemary amino acids inc1ude, for example, the auxiliary-controlled Strecker synthesis5 and the diastereoselective alkylation of chiral enolates.6 Being both an economic and a widely applicable strategy, the organocatalytic approach of Barbas lIJ, will be discussed in this chapter?
72. 60 4 BIRT-377 4.2 Key Chemistry: Organocatalysis Although it is a rather old topic, organocatalysis has attracted new attention and interest in the field of natural product synthesis. As for toxicity reasons heavy metal s have to be avoided in the last steps of the synthesis of pharmaceuticals, organocatalytic pathways are ofien an attractive altemative. Although the amounts of catalyst should rather be called substoichiometric than catalytic, these enantiopure catalysts bring advantages such as air and moisture stability as well as ease of availability in comparison to altemative organometallic catalysts. In addition, they can be reused more easily than their organometallic counterparts if they are anchored to solid support materials.8 Organocatalysis in general comprises processes that are promoted by an organic compound that comes out of the reaction unchanged. Today, for a great variety of reactions, organocatalytic variants have been developed, such as for aldol additions and condensations, Mannich reactions, Michael additions, Diels-Alder reactions or Baylis-Hillman reactions, among many others. 9 Of course, organocatalysts are as diverse as their applications and only a few of them can be discussed in more detail here. The most commonly used type of catalyst is a relatively small, bifunctional molecule that contains both a Lewis base and a BrfJnsted acid center, the catalytic properties being based on the activation of both the donor and the acceptor of the substrates. The majority of organocatalysts are chiral amines, e.g. amino acids or peptides. The acceleration of the reaction is either based on a charge-activated reaction (formation of an irnminium ion 4), or involves the generalized enamine catalytic cycle (formation of an enamine 5). In an imminium ion, the electrophilicity compared to a keton or an oxo­ Michael system is increased. If the imminium ion is deprotonated to form an enamine species, the nucleophilicity of the a-carbon is increased by the electron-donating properties of the nitro gen. 8 o A 2 4 5
73. 4 BlRT-377 61 For c1arity reasons, the enamine catalytic cyc1e, proposed by List et al.,9b,10 will be discussed with the help of an exemplary aldol addition, catalyzed by L-proline (6). The arrows may be considered equilibria. H20 O V t0 y'~X, R20R1 OH 9 ~-:?' R1 7 r R2 8 :j: V t0 ~o H OH (± )"H .?:::t~'R1 6 R2 "'- 10 'y,H O /X0Rl~ ~O TBSq. R2 '.-J 12 ~ "HO ~o ~y e H OH H20 "-1 13 R2 X~ Ph 11 NH Ph"" tN~O H OH 14 The catalyst 6 forms an imminium species (not shown) via a nuc1eophilic attack ofthe Lewis basic amine at the carbonyl moiety of I substrate 7. The imminium ion is deprotonated to give enamine 8. ~~~: Coordination of the electrophile 9, which can be an aldehyde, ketone 1~ or azodicarboxylate, leads to the transition state 10. In this way, the O facial orientation of the substrates is more or less fixed in a cyclic n N, conformation, depending on the steric- and electronic properties ofthe 'N~ I~ H HN-N constellation. The electron-donating properties of the nitro gen atom 16 then directs the addition to the electrophile that is saturated by the Bmnsted acid, in this case the carboxylic acidic proton. The great variety of different substrates for diverse applications has led to the development of a large assortment of catalysts. Sorne organocatalysts are depicted in the margin, among them 13 from the Hayashi group,ll 14 and 15 developed by Jergensen et al. 12 and 16 published by Ley and coworkers.13 The morpholin derivative 17 has been used by Barbas JIl and ChowdarF and MacMillan found manifold applications of 18, e.g. for enantioselective aldehyde­ aldehyde aldol coupling. 14
74. 62 4 BIRT-377 4.3 Overview
75. 4 BIRT-377 63
76. 64 4 BIRT-377 4.4 Synthesis Problem Hints • 21 is the solvent. • What kind of building block is needed to obtain 22? Think of a simple synthon and try to transform it into a reagent that could react with aldehyde 19! • Which functional group is needed? • As there are two aldehydes reacting, which carbon is the electrophile/nucleophile? How can you differentiate their reactivity? o Solution V 20 Discussion In this initial step, an aldol condensation takes place. The solvent of this reaction is an ionic liquido It is a very polar solvent that is able to stabilize polar molecules and can act as an acceptor for hydrogen bonds. Thus, it is able to shift the equilibrium towards the enol tautomers. After the aldol addition, the intermediate can eliminate water via a second enol intermediate. Although the substrates are both aldehydes, only one product is formed because 19 lacks an acidic position, so it cannot become a nuc1eophile. Owing to its tendency to form homodimers, a two-fold excess ofpropionaldehyde 20 is needed.
77. 4 BIRT-377 65 Problem • Which functionalities can be reduced under these conditions? Hints • Why is the Lewis acid employed? What might be its task? Solution I ,,?Y Brf) 23 The double bond and the aldehyde are reduced simultaneously under Discussion these conditions. The aluminum chloride is able to coordinate the oxygen and thus decreases the electron density of the Michael system. Lithium aluminum hydride is therefore able to reduce the C=C and the C=O double bonds. Problem • How many possibilities do you know for oxidizing an alcohol to Hints the corresponding aldehyde? • Think of their advantages and disadvantages. Which oxidation method would you try first?
78. 66 4 BIRT-377 Solution 1. DMSO, (COC1)2, NEt3, CH2C12, -60 oC, 30 min, 95 %. Discussion There are many methods for selectively oxidizing an alcohol to the corresponding aldehyde. Of course you have to think about the stability of your molecule when you decide which procedure to choose, but ecological and economic aspects are also very important. Chromium-free oxidations such as Swern conditions or Dess-Martin periodinane (DMP) are preferred over the classic methods that employ Jones reagent, Collins reagent or PCCIPDC. For the mechanism ofthe here used Swern protocol, see Chapter 5, p. 86. Problem Hints • First, the substrate's aldehyde functionality reacts with the catalyst 26 to form an imminium ion, which is deprotonated to give an enamine intermediate. • Draw the intermediate that is formed and the transition state with the bisdibenzyl azodicarboxylate! • Can you imagine what function the tetrazole residue could have, apart from blocking one face ofthe molecule? Solution 27
79. 4 BIRT-377 67 The tetrazo1e residue of the cata1yst is coordinated by one of the Discussion reagent's nitrogen atoms via a hydrogen bond. In the cyc1ic transition state, this coordination 1eads to a re1ative1y fixed conformation, which is important for the se1ectivity of the reaction. The initially formed imminium ion deprotonates to give the enamine. Upon e1ectron donation of the pyrrolidine nitrogen, the enamine adds to the N=N doub1e bond which is protonated by the tetrazo1e to form an a-modified imminium intermediate. After hydro1ysis, product 27 is formed. :j: 27 34 A number of organocata1ysts such as derivatives of proline and morpholine were screened by Barbas' group and the tetrazo1e cata1yst 26 gave the best result, with 95 % yie1d and 80 % ee. The enantiomerically enriched mixture cou1d be recrystallized to yie1d 71 % of aminoa1dehyde 27 in >99 % ee. Problem • What methods do you know to oxidize an a1dehyde function to the Hints corresponding carboxy1ic acid?
80. 68 4 BIRT-377 Solution 1. NaCI02, NaH2P04, 2-methyl-2-butene, t-BuOH/H20 5:1, 4 oC, 12 h, 86 %. Discussion Again, a chromium-free oxidation method is employed. Sodium chlorite oxidizes aliphatic or aromatic aldehydes. In the process it forms hypochloric acid (HOCl) or sodium hypochlorite (NaOCl), which are even more reactive than sodium chlorite and therefore must be quenched in situ by the olefinic additive 2-methyl-2-butene in an acidic buffer medium. Problem Hints • In this rather unusual esterification, both oxygen atoms come from the substrate 28. • Diazomethane is formed in situ from TMS-diazomethane. • The carboxylate reacts as a nuc1eophile in this case. • N2 is the leaving group. Solution 1. TMSCHN2, toluene/methano12:1, r.t., 10 min, 99 %. Discussion Trimethylsilyldiazomethane can be used for esterification reactions. 1S The free electron pair at the carbon atom of diazomethane, which is formed in situ from TMS-diazomethane (35), deprotonates the carboxylic acid 28 first. Under nuc1eophilic attack by the carboxylate oxygen on the methylene group of 37, nitrogen is expelled. This extremely good leaving group delivers the driving force for this reaction. In contrast to other esterification reactions, the methoxy oxygen is the former carboxylic one. The advantages of TMS­ diazomethane over diazomethane are a decreased toxicity and increased stability.
81. 4 BIRT-377 69 N O 111 11 N® ./'- + 1 ~O R jlCH2 ~8 28 35 29 Problem • The carbamate is to be transformed into the free amine in the next Hints tr.ree steps. In this first step, the nucleofugal properties of one carbamate nitrogen have to be improved to cleave the N-N bond in the second step. • TF AA is the abbreviation for trifluoracetic anhydride. • Which position is trifluoracetylated? Solution The trifluoracetylation is initiated by deprotonation of the primary Discussion carbamate nitrogen, which increases its nucleophilicity compared to the secondary one. The lone pair then atiacks the trifluoracetic anhydride.
82. 70 4 BIRT-377 Barbas 111 et al. report that the carbamate can only be c1eaved after trifluoracetylation in this case. Problem Hints • Row can trifluoracetylated hydrazine derivatives be c1eaved? • A lanthanoide is used in this reaction. Solution 1. SmI2, THF, 3 % MeOR, r.t., 30 mino Discussion Samarium iodide selectively c1eaves trifluoracetylated hydrazines.16 Since direct c1eavage of the N-N bond in 30 did not work with samarium iodine, it was necessary to trifluoracetylate the carbamate first. Problem
83. 4 BIRT-377 71 • Can the ester be cleaved under these conditions? Hints • Is the carbamate stab1e? • This is a standard procedure for the deprotection of carboxybenzy1 (Cbz) groups. • Try to propose a mechanism! o Solution Meo?\NH2 9Sr 32 The methy1 ester is stab1e under these conditions as there is no Discussion nucleophi1ic hydroxy1 function. The Cbz deprotection is initia1ized by protonation of the carbamate's carbony1 oxygen. Br- is a good nucleophi1e; it atiacks the benzylic methy1ene carbon, and cleavage of the benzy1ic C-O bond follows. The unsubstituted hydrogen carbamate is not stab1e; carbon dioxide is 10st, de1ivering the driving force ofthis reaction. HRN'y"'O" H® HRN O {sr8 HRN~O 11 1 ;¡("-./1 - I HRN-H O Ph ~OH Ph OH -C02 ® 31 38 39 32 40
84. 72 4 BIRT-377 Problem Hints • Have a look at the product. Do you recognize the former amine nitro gen and ester carbonyl group? • Mark the new atoms in the heterocycle ofthe product! • What kind of reaction must have taken place? • What kind ofreactant is needed? Solution 1. 41, Na2C03, DMSO, r.t., 1 h, 99 %. OeNyyely el 41 Discussion The amino acid ester forms the hydantoin 33 with the isocyanate 4l. The free amine 32 attacks the isocyanate carbon and the nucleophilic isocyanate nitro gen in 42 then reacts with the electrophilic ester moiety. The carbonate base prevents protonation ofthe amine.
85. 4 BIRT-377 73 32 41 o R',- J{ N NH O~ 33 Problem • What kinds of methylating reagents do you know? Hints l. MeI, LiHMDS, DMF, r.t., 3 h, 94 %. Solution The hydantoin is deprotonated with the non-nuc1eophilic base Discussion LiHMDS. Thus, the nuc1eophilicity of the nitrogen is increased. It attacks the iodomethane in an Swtype reaction to give 1 in 94 % yield.
86. 74 4 BIRT-377 4.5 Conclusion Barbas JII et al. describe the enantioselective synthesis of BIRT- 377 (1) in 11 steps with an overall yield of 35 %, which is an average yield of91 % per step. Starting from two achiral aldehydes, the substrate for the organoeatalytie key step is built up in three steps. The aminofunetion is then introdueed by a seleetive organoeatalyzed a-addition of this aldehyde to an azodiearboxylate moiety. In this way, the quatemary stereogenie eenter of an a-aminoaldehyde is built up eatalytieally without the need of any ehiral auxiliary. After c1eavage of the N-N bond and Cbz deproteetion, the heteroeyc1e is built up via a eyelization of the a-aminoester and an aromatie isoeyanate. Methylation of the now eyc1ie amine completes this effeetive natural produet synthesis. The applieation of an organoeatalytie method for the generation of the quatemary a-aminoaldehyde shows that organoeatalysis can be an attraetive altemative to c1assieal methods e.g. the auxiliary eontrolled Strecker synthesis. Introducing the ehiral information eatalytieally can c1ear1y be an advantage eompared to a stoiehiometrie ehiral pool approaeh, especially when the stereogenie eenter eannot be derived from a natural amino aeid. 4.6 References a) T. A. Kelly, D. D. Jeanfavre, D. w. MeNeil, J. R. Woska, Jr., P. L. Reilly, E. A. Mainolfi, K. M. Kishimoto, G. H. Nabonzny, R. Zinter, B.-J. Bormann, R. Rotlein, J. Immunol. 1999, 163, 5173-5177; b) J. R. Woska, Jr., M. M. Moreloek, D. D. Jeanfavre, B.-J. Bormann, J. Immunol. 1996,156,4680-4685; e) J. R. Woska, Jr., K. Last-Bamey, R. Rotlein, R. R. Kroe, P. L. Reilly, D. D. Jeanfavre, E. A. Mainolfi, T. A. Kelly, G. O. Caviness, S. E. Fogal, M. J. Panzenbeek, T. K. Kishimoto, P. A. Giblin, J. Immunol. Methods 2003, 277,101-115. 2 R. S. Larson, T. Davis, C. Bologa, G. Semenuk, S. Vijayan, Y. Li, T. Oprea, A. Chigaef, T. Buranda, C. R. Wagner, L. A. Sklar, Biochem. 2005,44,4322-4331. 3 a) M. R. Nicolls, M. Coulombe, J. Beilke, H. C. Gelhaus, R. G. Gill, J. Immunol. 2002, 169, 4831-4839; b) R. S. Poston, R. C. Robbins, B. Chan, P. Simms, L. Presta, P. Jardieu, R. E. Morris, Transplantation 2000,69,2005-2013; e) S. Sarnaeki, F. Auber,
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88. 76 4 BIRT-377 Catal. 2004, 346, 1435-1439; b) H. Ohtak:e, Y. Imada, S.-I. Murahashi, Bull. Chem. Soco Jpn. 1999, 72,2737-2754. 12 a) N. Halland, R. G. Hazell, K. A. JlMgensen, J. Org. Chem. 2002, 67, 8331-8338; b) N. Halland, T. Hansen, K. A. JlMgensen, Angew. Chem. 2003, 115, 5105-5107; Angew. Chem. Int. Ed. 2003,42,4955 4957. 13 J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V. Ley, Org. Biomo!. Chem. 2005, 3, 84-96. 14 K. Mangion, A. B. Northrup, D. W. C. MacMillan, Angew. Chem. 2004, 116, 6890-6892; Angew. Chem. Int. Ed. 2004, 43, 6722-6724. 15 a) N. Hashimoto, T. Aoyama, T. Shioiri, Chem. Pharm. Bull. 1981, 29, 1475-1478; b) M. Miwa, T. Aoyama, T. Shioiri, Synlett 1994, 107-108; e) M. Miwa, T. Aoyama, T. Shioiri, Synlett 1994, 109-110; d) F. Matsuura, Y. Hamada, T. Shioiri, Tetrahedron 1994, 50, 11303-11314; e) A. Presser, A. Hüfner, Monatsheftefür Chemie 2004,135,1015-1022. 16 H. Ding, G. K. Friestad, Org. Lett. 2004,6,637-640.