Organic synthesis workbook III

He is now doing his doctoral research in the same group studying palladium-catalyzed enantioselective domino-reactions for the synthesis of chromanes.. She stayed in the same group for h

F Stecke r , N Tólle , J Zinngrebe

Organic Synthesis

Tom Kinzel, Felix Major,

Thomas Redert, FIarían 5tecker, Julia Zinngrebe, Nina Talle, and Christian Raith

Organic Synthesis Workbook 111

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The Authors

Organic Synthesis Workbook 1 JI

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 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

re-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 ber 2003 under the guidance ofProfessor Lutz F Tietze

Septem-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, many, and started studying chemistry at the University

Ger-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

Tom Kinzel Felix Major, Thomas Redert, Florian Stecker, Julia Zinngrebe, Nina Tolle Christian Raith Copyright © 2007 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim

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, 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

re-VI, France, under the direction of Professor Max cria in 2002/2003 Shortly thereafter, he joined the group of Professor Lutz F Tietze in Gottingen, where

MaIa-he is currently a doctoral researcMaIa-her He is committed

to the palladium catalyzed domino-Wacker-Heck 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

reac-of Prreac-ofessor 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, 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

Ger-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

Dedicated to our PhD supervisor Pro! Dr Dr h c L F Tietze

on the occasion ofhis 65th birthday

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 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

Bio-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

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

Minfiensine (1) was first isolated by Massiot and coworkers in 1989

from Strychnos minfiensisi, S potatorum and S longcaudata 1 The

unique 1 ,2,3,4-tetrahydro-9a,4a-(iminoethano )-9H-carbazole motif (4)

is also present in related alkaloids/ exemplified by 2 and 3, which are

composed of tryptamine and monoterpene units, presumably being

derived in nature from cyc1ization of corynantheine derivatives.3 As

several biological activities have been associated with these

alka-10ids,2.4 inc1uding promising anticancer activity, a concise,

enantio-selective chemical synthesis entry to the unique structural motif 4

would allow further exploration of the pharmacology of this

interest-ing c1ass of alkaloids

(Hydroiminoethano)-9H-carbazoles 4 having a 1,2 or 2,3 double bond

were seen as potentially versatile platforms for constructing alkaloids

of this type, as a bridging ethylideneethano unit between the

pyr-rolidine nitrogen and C-2 or C-3 would form the pentacyc1ic ring

skeleton found in these alkaloids.5

This chapter is based on an approach by Overman and coworkers who

completed the first enantioselective total synthesis of (+ )-minfiensine

1,2,3,4-tetrahydro-9a,4a-The Heck reaction

R1: aryl, alkyl

x: 1, Br, CI, OTf (=OSO,CF 3)

Ovennan"s first asymmetric Heck reaction

° r O T f Pd(OAc), (R,R)-DIOP (10 mol-%) (10 mol-%) O i1 _

reaction has emerged as a reliable method for the stereoselective formation of tertiary and quatemary stereogenic centers by C-C bond formation in polyfunctionalized molecules.9,1O,11

The basic mechanism ofthe Heck reaction (as shown below) of aryl or

aIkenyl halides or triflates involves initial oxidative addition of a ladium(O) species to afford a a-arylpalladium(I1) complex 111 The order of reactivity for the oxidative addition step is 1 > OTf> Br > Cl Coordination of an aIkene IV and subsequent carbon-carbon bond formation by syn addition provide a a-alkylpalladium(I1) intermediate

pal-VI, which readily undergoes ~-hydride elimination to release the product VIII A base is required for conversion of the hydridopalla-dium(I1) complex IX to the active palladium(O) catalyst I to complete the catalytic cycle

reductive elimination

H R2

VI

R2 = alkenyl, aryl, alkyl, C02R', OR', SiR'3

X = 1, Br, CI, OS02CF3, S02CI, COCI, 1+(OAc), OS02F, OPO(ORh

1 Minjiensine

A variety of palladium(I1) and palladium(O) complexes serve as

effec-tive precatalysts or precursors to the aceffec-tive palladium(O) catalyst The

most commonly used precatalysts in Heck chemistry are Pd(OAc)z,

Pd2(dba)3, and PdCh(PPh3)z Typical catalyst loading is in the range of

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

Beller 12 has set a milestone in palladium catalysis as it allows the use

of even unreactive chloroaryl substrates in Heck transformations

A variety of chiral phosphine ligands are frequently used for

asym-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

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

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

the Heck reaction is expected to proceed through a "neutral" reaction

pathway The modest enantioselectivity ofien observed in Heck

reactions of this type has been attributed to the formation of a neutral

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-siso For intramolecular Heck reactions, regiocontrol in the migratory

insertion step is largely govemed by the size of the ring being formed

Poor regioselectivity in the ~-hydride elimination step limits the use of

the asymmetric Heck reaction for the construction of tertiary

stereo-centers The use of cyclic aIkenes as substrates prevents the formation

of the undesired double-bond isomer during the ~-hydride elimination

step However, Tietze and coworkers have demonstrated that this main

disadvantage of the Heck reaction can be overcome by using an

allylsilane as the terminating aIkene component.13 This procedure

allows the regioselective formation of tertiary stereogenic centers even

from acyclic alkenes

An additional concem arises from the reversibility of the ~-hydride

elimination step The hydridopalladium(I1) species is formed upon

re-adds across the initially generated double bond of the product

Depending upon the regio- and stereochemistry of this

hy-dropalladation step, subsequent ~-hydride elimination could

regener-ate either the initial Heck product or a regioisomer thereof.9,1O,1l

j

[ 0]+ R, "Pd

L 2 XHP1 C)o

1.3 Overview

1 Minjiensine 5

6

1 Minjiensine

• Sodium hexamethyldisilazide (NaHMDS) is a sterically

deman-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 Ci)::)

I Me02C

9

The sodium salt of enamine 8 is formed by deprotonation with

NaHMDS followed by selective N-protection with methyl

chloro-formate at -78 oC to give carbamate 9 in 52-60 % yield

• Comins' reagent is a reagent to introduce triflate moieties

• The triflate of the kinetic enolate is formed

!riHuoro-Hints

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

• 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

12

1 Minfiensine

The introduction of the aminoethyl side chain is accomplished by

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 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

the margino The mechanism involves oxidative addition of an alkenyl

or aryl triflate (R-X) to the initial palladium(O) complex to form a

palladium(I1) species In most cases, the rate-determing step is

transmetallation, so called because the nucleophile is transferred from

the metal in the organometallic reagent to the palladium The new

palladium(I1) complex with two organic ligands undergoes reductive

elimination to give the cross-coupled product and the palladium(O)

catalyst is regenerated for another catalytic cycle.!O·ll

• The aryl triflate 13 is forrned in one step from silyl ether 12

• 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

Aryl triflate 13 is obtained by reaetion of silyl ether 12 with CsF,

CS2C03 and Comins' reagent at room temperature Under these

reae-tion eondireae-tions the TIPS-ether is c1eaved to provide the eorresponding

phenolate, whieh undergoes reaetion with Comins' reagent to give

triflate 13 in a one-pot protoeol

• In this reaetion 14 is used as an enantiopure ehiralligand for dium(O)

palla-• 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

1 Minjiensine

Initial experiments showed that the asymmetric Heck cyclization of 13

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

Problem

Hints

Solution

Discussion

Upon addition of excess trifluoroacetic acid to the crude Heck

pro-duct, an iminium ion cyclization fumishes the tetracyclic core of fiensine (1) without cleavage ofthe Boc group

min-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 crystal X-ray analysis of a heavy-atom derivative.5

single-• 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)

17

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

1 Mirifiensine

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

• Alkyl phenyl selenoxides bearing a ~-hydrogen undergo syn

elimi-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

18

Alkyl phenyl selenoxides bearing a ~-hydrogen undergo faeile syn

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

"away" from the hydroxyl group Thus, in most cases, no more than traces ofthe possible carbonyl product are observed.20

After deprotonation with imidazole, the allylic alcohol is protected as

a silyl ether

• 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

secon-1 Minfiensine

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

19

oxidative addition

15

• First, the silyl protective group is cleaved

• Oxidation of the free secondary alcohol provides a ketone

• Enolates are versatile intermediates for functionalization of tions ato carbonyl groups

posi-1 TBAF, THF, r.t., 100 %

2 DMP, CH2Cb, r.t., 99 %

3 CNC02Me, LiHMDS, THF, -78 oC, 71 %

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

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

represents a 1,3-dicarbonyl compound that preferentially exists in the enol formo

The use of methyl cyanoformate allows the selective C-acylation of ketones in a regioselective manner to give p-keto ester derivatives 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

1 Mirifiensine

• This sequence commences with a chemoselective reduction

• 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 %

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

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

Problem

Hints

Solution

Discussion

• 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

1 LiAlH4, 11IF, -20 oC, 89 %

2 NaOH, MeOHlH20, 100 oC, 95 %

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 kaloids containing the 1 ,2,3,4-tetrahydro-9a,4a-(iminoethano )-9H-

al-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

1 Minfiensine

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

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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

biosynthesis pathway It has been argued that the somewhat unusual

exo-methylene group at C-6 in myriaporones 1 (1) and 2 (2) is a result

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-genic centers are present Similar to carbohydrates such as glucose,

the molecule can cyc1ize to form a six-membered hemiacetal that

exists in equilibrium with the open-chain formo Nevertheless, both

constitutions of the natural product have been assigned different

names, namely myriaporone 4 (4) and myriaporone 3 (3) for the

open-chain and the cyc1ic isomer, respectively

To date, two total syntheses of myriaporone 4 are known,z This

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-tions and additionally inc1udes reductionloxidation steps as well as

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

Zimmermann- T rax/er transition state with

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 Z-configured enolates give the syn isomer This rule can be derived

from the Zimmerman-Traxler model5, which assumes the cyclic membered transition states 8 or 9 (M = enolate counterion)

six-The term "induced selectivity" addresses the question of the absolute stereochemistry of the fmal product To achieve good induced selectivity (for any reaction), three conditions need to be fulfilled:

1 There must be enantiopure chiral information in the stereoselective step This can be achieved either by using covalent attachment to one of the substrates (stereoselective auxiliary-based methods) or

by creating a complex that is cleaved after the stereoselective elementary step under the reaction conditions and reused for the next molecule (stereoselective catalytic methods) Substrate control is observed when the substrates themselves are chiral,

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

Evans and coworkers have developed chiral oxazolidinone auxiliaries

such as 10 and 11 that are easily obtainable from (S)-vanilol or from (IS,2R)-norephedrine.4a As well as the excellent selectivities obtained

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

is to be enolized Because of chelation of the enolate counterion to the auxiliary carbonyl oxygen, the auxiliary is fixed and prevents formation of E-configured enolates 13; only Z-configured enolates 12

are obtained Therefore, normally only syn-configured aldol products

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 NEt and R BOTf as

2 Myriaporone 4

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

By changing the counterion it is possible to obtain either one or the

other isomer of the desired aldol product

There are several ways to cleave the auxiliary ftom the product 7

Typical reactions inc1ude reduction with complex hydrides such as

LiBIl¡ to obtain the alcohol 18 or transamination to the Weinreb

amide and subsequent reduction with DIBAL to give the aldehyde 19

that would have been obtained ftom direct aldol reaction.6