Organic synthesis workbook III

T. Kinzel , F. Major, C. Raith , T. Redert,
F. Stecker, N. Tólle, J. Zinngrebe

G?WllEY-VCH

Organic Synthesis
Workbook 111
Foreword by Matthias Beller


Tom Kinzel, Felix Major,
Thomas Redert, FIarían 5tecker,
Julia Zinngrebe, Nina Talle,
and Christian Raith
Organic Synthesis Workbook 111


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, enabling 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
President and Chief Executive Officer

Peter Booth Wiley
Chairman of the Board


Tom Kinzel, Felix Major, Thomas Redert, Florian Stecker,
Julia Zinngrebe, Nina Talle, and Christian Raith

Organic Synthesis Workbook 111

BICENTENNIAL
.J

iz

•

o 7 z~
~z @WILEY z~
~
•

1 8

2007

~
>
r

WI LEY-VCH Verlag GmbH

& Co.

KGaA


The Authors
Tom Kinzel, Felix Major, Thomas Redert,
F/orian Stecker, Julia Zinngrebe, Nina Tlille,
Christian Raith

U niversity of Giittingen
Institute for Organic and Biomolecular
Chemistry
Tammannstr. 2
37077 Giittingen
Germany

All books published by Wiley-VCH are careful1y produced. Nevertheless, authors, editors,
and publisher do not warrant the information

contained in these books, including this
book, to be free of errors. Readers are advised
to keep in mind that statements, data, illustrations, procedural detalls or other items
may inadvertently be inaccurate.
Library of Congress Card No.: Applied for
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 Nationalbibliografie; detailed bibliographic data are available in the Internet at <>.
© 2007 WILEY-VCH Verlag GmbH & Co.
KGaA, Weinheim
All rights reserved (including those of translation 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 permission 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
Anne Christine Kegler,

Grafik-Designerin, Karlsruhe
Wiley Bicentennial Logo Richard
Cover

J.

Paófico

Printed in the Federal Republic of Germany.
Printed on aód-free papero
ISBN:

978-3-527-31665-6


The Authors
Tom IGnzel, born in 1977 in Erfurt, Germany, started

studying chemistry at the University of Giittingen, Germany, in October 1998. After staying in the Peoples Republic of China in 2001/2002 studying Chinese at the University ofNanjing and joining the working group ofProfessor
Wolfgang Hennig at the Chinese Academy of Sciences in
Shanghai, he returned to Giittingen and received his diploma in Chemistry in July 2004. He is now a doctoral researcher 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 Giittingen, 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 September 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 biological evaluation of prodrug analogues of the antibiotic
CC-1065 for a selective treatment of cancer.
Christian Raith was born in 1980 in Giittingen, Germany, 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 dominoreactions 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


Thomas Redert, bom in 1978 in Gieí?en, Germany,
started studying chemistry at the University of Gottingen, Germany, in October 1999. After staying in the
United Kingdom in 2002/2003 at the University ofNewcastle 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 dominocyclizations for the synthesis of natural product analogues.
FIorían Stecker, bom in 1980 in Eutin, Germany, received his diploma in organic chemistry from the University 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 MaIacria 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 reaction 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 Gottingen, 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 dominoreactions for the synthesis of spiroamine structures with
the objective of natural product synthesis.
Dr. Julia Zinngrebe, bom in 1979 in Eschwege, Germany, 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-reactions 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 Biomolecular Chemistry ofthe Georg-August-University ofGottingen, Germany.1t covers 14 wellselected synthetic problems including modern catalytic coupling reactions and metathesis
chemistry, together with recent developments in stereoselective carbon-carbon and carbonoxygen 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



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



Contents

O::tLr'0H
t\

Chapter 1
Mienfiensine
(Ovennan 2005)

N~,

1

~

HN~

Key Chemistry: Enantioselective Heck Reactions

Chapter 2
Myriaporone 4
(Taylor 1998,2004)

21

Key Chemistry: Evans Aldol Reactions

Chapter 3
Ningalin D
(Boger 2005)

41

HO

Key Chemistry: Pyrrole Synthesis using a 1,2,4,5-Tetrazine ~ 1,2-Diazine ~ Pyrrole Strategy

Chapter4
BIRT-377
(Barbas 2005)

59

Key Chemistry: Organocatalysis

Chapter 5
Vitamin E
(Tietze 2006)
Key Chemistry: Palladium(II)-catalyzed Domino Wacker-Heck Reaction

77

Chapter 6
(+)-Cyanthiwigin U
(Phillips 2005, Palomo 2002)

93

Key Chemistry: Alkene Metathesis

Chapter7
ZK-EPO
(Schering AG 2006)

113

Key Chemistry: Macrolactonization

Chapter 8
(+)-Laurenine
(Boeckmann 2002)

139

Key Chemistry: Enantioselective Reduction ofKetones

Chapter 9
Cylindramide
(Laschat 2005)

157

Key Chemistry: Oxidation ofketones to the corresponding
via the silyl enol ether

Chapter 10
Peridinin
(Bruckner 2006)

u,~-unsaturated

carbonyl compounds

175

~~

ACO~

Key Chemistry: Formation of C=C double bonds

o


193

Chapter 11
Laulimalide
(Mulzer 2003)

Key Chemistry: Asyrnmetric Epoxidation of Alkenes

217

Chapter 12
Cystothiazole B
(Panek 2004)
Key Chemistry: Stereoselective Crotylation of Aldehydes with Chiral Crotyl Silanes

233

Chapter 13
(+)-Pentacycloanammoxic acid
(Corey 2006)
Key Chemistry: Photochemical Cycloadditions

Chapter 14
(-)-Dactylolide
(McLeod 2006)

253
o

Key Chemistry: [3,3]-Sigmatropic Ireland-Claisen Rearrangement

Abbreviations

277

Index

279



~

1

~OH
N:.,

::.

HN~

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
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 alka10ids,2.4 inc1uding promising anticancer activity, a concise, enantioselective chemical synthesis entry to the unique structural motif 4
would allow further exploration of the pharmacology of this interesting 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 pyrrolidine 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) in 2005. 5

;\

Ccf1r"0H
ó

N~,

HN~

Minfiensine

~ HO~02Me

Q::Wy
I

Me

W'I

Me

OH

2
Echitamine
C0 2 Me

Meo'Ccib~
N -'~
I
N
Me

3
Vincorine

9a,) 2
CcW
1,&
;\'

4a

N~,

3

H N
H

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

2

1

Minfiensine

1.2 Key Chemistry: Enantioselective Heck
Reactions
Mizorok¡.fJa and Heck6b reported independently in the early 1970s the

The Heck reaction

R1: aryl, alkyl

x: 1, Br, CI, OTf (=OSO,CF3)

Ovennan"s first asymmetric Heck reaction

i1

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

_

Et3N, benzene, r.t.

,.-'

90 %, 45 % ee

~
Shibasakts first group-selective Heck reaction

Pd(OAc), (3 mol-%)
(R)-BINAP (9 mol-%)

C~Me
~e
cYJ
I-----~
A
cyclohexene (6 mol-%)

,y
...9

I

Ag2 C03

(2 equiv.)

NMP, 69'C

~

¿

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
reactions by Overman7 and Shibasaki8 in 1989 the asymmetric Heck
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 palladium(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
VI, which readily undergoes ~-hydride elimination to release the
product VIII. A base is required for conversion of the hydridopalladium(I1) complex IX to the active palladium(O) catalyst I to complete
the catalytic cycle.

74%,46% ee

Base' HX

Base~

reductive
elimination

[Pd(O)L2]
I

~ (R~t

[H-Pd(II)L2-X]

R~~2

internal

r:

~R2

IV
coordination

R1-Pd(II)L 2-X

-==--R2

R2

rotatio~

addition

111

syn f3-hydride
elimination
H:\__ld(II)L2-X
VII

~

R1-Pd(II)L2-X

::¡IX
R1

oxidative

V

R}_ld(II)L2-X

/.yn insertion

R2

H
VI

R 1 = alkenyl, aryl, benzyl, alkynyl
R2 = alkenyl, aryl, alkyl, C0 2R', 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 effective 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(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 asymmetric 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 synthesiso 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 stereocenters. 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
~-hydride elimination and there is the possibility that this complex readds across the initially generated double bond of the product.
Depending upon the regio- and stereochemistry of this hydropalladation step, subsequent ~-hydride elimination could regenerate either the initial Heck product or a regioisomer thereof. 9 ,1O,1l

3

Hemnann-Beller catalyst

PR2
PR2

(R)·BINAP

phosphinooxazoline

(R,R}-OIOP

o
Pd

R 'x

cationic ~ "
pathway

neutral

pathway

-'K

[9r
11

[Q]+
R~

j

[ 0]+
R,--"Pd

R

o
Pd

'--" X

Il-hydnde

elimination

L2XHPd"{::)O

¡R
1

hydropalladation

1

L2XHP

~-hydride

C)o
R1

elimination

H

XL2 Pd,·,CO

R1


4

1

1.3

Minfiensine

Overview

1

Minjiensine

5


6

Mirifiensine

1

1.4

Synthesis

Problem

()
N
H

morpholine

Hints

•

•

Morpholine is a secondary, cyc1ic amine which reacts with aldehydes and ketones to give enamines with the formation of water.
The morpholine enamine reacts in an acid-catalyzed transamination with 2-siloxyaniline 7.

TIPSO O

Solution

elN!:)
H

8

Discussion

The enantioselective total synthesis of 1 commences with the formation 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-aminophenol, reacts with the morpholine enamine 15 in an acid-catalyzed transamination to give enamine 8.

::0
6

7


1

Minjiensine

7
Problem

•
•
•
•

Hints

Sodium hexamethyldisilazide (NaHMDS) is a sterically demanding 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
NaHMDS followed by selective N-protection with methyl chloroformate at -78 oC to give carbamate 9 in 52-60 % yield.

Discussion

Problem
CI~

t.A
N
N(Tf)z

Comins' reagen!

TI: !riHuorome!hylsulfonyl

•
•

Comins' reagent is a reagent to introduce triflate moieties.
The triflate of the kinetic enolate is formed.

Hints


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(trifluoromethylsulfonyl)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