Organocatalysis Episode 1 doc

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany e-mail: reetz@mpi-muelheim.mpg.de List, B.. Max-Planck-Institut für Kohlenforschung, K

Ernst Schering Foundation Symposium Proceedings 2007-2

Organocatalysis

Ernst Schering Foundation Symposium Proceedings 2007-2

Series Editors: G Stock and M Lessl

Library of Congress Control Number: 2007943075

ISSN 0947-6075

ISBN 978-3-540-73494-9 Springer Berlin Heidelberg New York

This work is subject to copyright All rights are reserved, whether the whole or part

of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag Violations are liable for prosecution under the German Copyright Law.

Springer is a part of Springer Science+Business Media

springer.com

© Springer-Verlag Berlin Heidelberg 2008

The use of general descriptive names, registered names, trademarks, etc in this publication does not emply, even in the absence of a specific statemant, that such names are exempt from the relevant protective laws and regulations and therefor free for general use Product liability: The publisher cannot guarantee the accuracy any information about dosage and application contained in this book In every induvidual case the user must check such information by consulting the relevant literature.

Cover design: design & production, Heidelberg

Typesetting and production: le-tex publishing services oHG, Leipzig

21/3180/YL – 5 4 3 2 1 0 Printed on acid-free paper

Chemical synthesis is one of the key technologies that form the basis

of modern drug discovery and development For the rapid preparation

of new test compounds and the development of candidates with oftenhighly complex chemical structures, it is essential to use state-of-the-art chemical synthesis technologies Due to the increasing number ofchiral drugs in the pipeline, asymmetric synthesis and efficient chiralseparation technologies are steadily gaining in importance Recently

a third class of catalysts, besides the established enzymes and metalcomplexes, has been added to the tool kit of catalytic asymmetric syn-thesis: organocatalysts, small organic molecules in which a metal is notpart of the active principle

Despite considerable efforts to explore and extend the scope of metric organocatalytic reactions in recent years, their use in medicinaland process chemistry is still rather low This is even more surpris-ing as the field was pioneered by the medicinal chemistry laboratories

asym-of Schering AG and Hasym-offmann La Roche in the late 1960s and early1970s by using proline as asymmetric catalyst in a Robinson annulation

to obtain steroid CD ring fragments, a process now referred to as theHajos–Parrish–Eder–Sauer–Wiechert reaction

In an effort to increase the awareness within the community of inal and process chemists, and to learn more about recent progress inthis rapidly evolving field, the Ernst Schering Foundation enabled us to

medic-VI Preface

organize a symposium on ‘Organocatalysis,’ which took place in Berlin,Germany, from 18 to 20 April 2007 The proceedings of this symposiumare detailed in this book

S.C Pan and B List’s paper spans the whole field of current alysts discussing Lewis and Brønsted basic and acidic catalysts Start-ing from the development of proline-mediated enamine catalysis—the Hajos–Parrish–Eder–Sauer–Wiechert reaction is an intramoleculartransformation involving enamine catalysis—into an intermolecular pro-cess with various electrophilic reaction partners as a means to access

organocat-α-functionalized aldehydes, they discuss a straightforward

classifica-tion of organocatalysts and expands on Brønsted acid-mediated formations, and describe the development of asymmetric counteranion-directed catalysis (ACDC)

trans-Impressive applications of chiral amine organocatalysts in naturalproduct synthesis come from the D Enders’ laboratory Enders and col-leagues elegantly employ the different modes of enamine and iminiumactivation in domino reactions leading to highly functionalized cyclo-hexenes Using dihydroxyacetone acetonide the amine organocatalystfunctions like an artificial aldolase eventually leading to carbohydrates,sphingolipids, and carbasugars In the following chapter, M Christmannreports examples for organocatalytic key steps in the total synthesis ofthe terpene alkaloid and telomerase inhibitor UCS1025A

More examples for ‘applied organocatalysis’ are presented by

H Gröger, who gives an overview of organocatalytic methods alreadyapplied on a technical scale Based on case studies, he shows severalexamples that satisfy the criteria of a technically feasible process such

as high catalyst activity and stability, economic access, sustainability,atom economy, and high volumetric productivity

Another privileged class of Lewis basic organocatalysts are ophilic carbenes, which have been proven to be extremely versatilefor different transformation, albeit strongly depending on the elec-tronic and steric nature of the catalyst F Glorius and K Hirano ap-

nucle-ply N-heterocyclic carbenes (NHC) for a conjugate umpolung of

α,β-unsaturated aldehydes into homoenolates, which are then reacted withaldehydes or ketones toγ-butyrolactones or β-lactones A review on

N-heterocyclic carbenes as a class of organocatalysts beyond the

by T Bach and coworkers An organocatalyst derived from Kemp’s acidinteracts with the secondary lactam or amide functionality of the sub-strates through double hydrogen bond contacts This is an addition tothe covalent involvement of amine organocatalysts, and allows for opti-mizing the stereochemical outcome by using nonpolar solvents, such astrifluorotoluene Hydrogen bonding networks in chiral thiourea cataly-sis are also elegantly used by A Berkessel in the kinetic resolution ofoxazolones and oxazinones.

Various aspects of organocatalysis with larger molecules are also ered in this book Possible benefits from immobilization approaches fororganic catalysts are pointed out by M Benaglia Apart from catalystrecycling or simplified workup procedures, catalyst immobilization can

cov-be additionally advantageous in terms of catalyst development and mization The use of soluble supports, such as polyethylene glycol, oftenallows the direct transfer and application of already optimized reactionconditions

opti-In the field of enzyme catalysis, some of the major drawbacks, such

as narrow substrate scope, or low selectivity and thermostability, can besuccessfully addressed by using directed evolution In contrast to a ra-tional design which uses site-specific mutagenesis, these studies utilizegenomic technologies like saturation mutagenesis and gene shuffling

to create powerful, tailor-made proteins as large molecule lysts An even more effective strategy to enhance enzyme catalysis is thesymbiosis of rational design and randomization, as applied in CASTing(combinatorial active-site saturation test) in combination with iterativesaturation mutagenesis which was introduced by M.T Reetz

organocata-VIII Preface

Although organocatalysis is still in its infancy compared to catalyzed processes or enzyme-mediated transformations, there has beentremendous progress within the last few years New reactions have beendeveloped and applied for technical processes Novel types of cata-lysts are constantly introduced expanding the scope of organocatalyticmethodology Moreover, increasing mechanistic insights will help to fur-ther improve known catalytic transformations and to exploit reactivity.The Ernst Schering Foundation workshop offered a broad overview onorganocatalytic processes, mechanisms and possible applications andprovided an outlook for the future establishment of organocatalysis

metal-as a third important strategy in metal-asymmetric catalysis, complementingmetal- and biocatalysis not only in academia, but also in industry Theeditors would like to acknowledge the generous support of the ErnstSchering Foundation, which allowed us to set up this exciting work-shop We trust that the readers will share the enthusiasm and excitement

in the rapidly expanding field of asymmetric organocatalysis

Manfred T Reetz

Benjamin List

Stefan Jaroch

Hilmar Weinmann

New Concepts for Organocatalysis

S.C Pan, B List 1Biomimetic Organocatalytic C–C-Bond Formations

D Enders, M.R.M Hüttl, O Niemeier 45Organocatalytic Syntheses of Bioactive Natural Products

M Christmann 125Asymmetric Organocatalysis on a Technical Scale:

Current Status and Future Challenges

H Gröger 141Nucleophilic Carbenes as Organocatalysts

F Glorius, K Hirano 159

N-Heterocyclic Carbenes: Organocatalysts Displaying

Diverse Modes of Action

K Zeitler 183

X Contents

New Developments in Enantioselective Brønsted Acid Catalysis:Chiral Ion Pair Catalysis and Beyond

M Rueping, E Sugiono 207Chiral Organocatalysts for Enantioselective

Photochemical Reactions

S Breitenlechner, P Selig, T Bach 255Organocatalysis by Hydrogen Bonding Networks

A Berkessel 281Recoverable, Soluble Polymer-Supported Organic Catalysts

M Benaglia 299Controlling the Selectivity and Stability of Proteins

by New Strategies in Directed Evolution:

The Case of Organocatalytic Enzymes

M.T Reetz 321

List of Editors and Contributors

Editors

Reetz, M.

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,

45470 Mülheim an der Ruhr, Germany

(e-mail: reetz@mpi-muelheim.mpg.de)

List, B.

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,

45470 Mülheim an der Ruhr, Germany

XII List of Editors and Contributors

Dipartimento di Chimica Organica e Industriale –

Universit´a degli Studi di Milano, Via C Goli 19, 20133 Milan, Italy(e-mail: maurizio.benaglia@unimi.it)

Berkessel, A.

Department of Organic Chemistry, University of Cologne,

Greinstraße 4, 50939 Cologne, Germany

Breitenlechner, S.

Lehrstuhl für Organische Chemie I, Technical University Munich,Lichtenbergstr 4, 85747 Garching, Germany

Christmann, M.

Institute of Organic Chemistry, RWTH Aachen University,

Landoltweg 1, 52074 Aachen, Germany

(e-mail: christmann@oc.rwth-aachen.de)

Enders, D.

Institute of Organic Chemistry, RWTH Aachen University,

Landoltweg 1, 52074 Aachen, Germany

(e-mail: Enders@rwth-aachen.de)

Glorius, F.

Organisch-Chemisches Institut,

Westfälische Wilhelms-Universität Münster,

Corrensstraße 40, 48149 Münster, Germany

(e-mail: glorius@uni-muenster.de)

List of Editors and Contributors XIII

Westfälische Wilhlems-Universitat Münster,

Corrensstraße 40, 48149 Münster, Germany

(e-mail: khirano@uni-muenster.de)

Hüttl, M.R.M.

Institute of Organic Chemistry, RWTH Aachen University,

Landoltweg 1, 52074 Aachen, Germany

List, B.

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,

45470 Mülheim an der Ruhr, Germany

(e-mail: list@mpi-muelheim.mpg.de)

Niemeier, O.

Institute of Organic Chemistry, RWTH Aachen University,

Landoltweg 1, 52074 Aachen, Germany

Pan, S.C.

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,

45470 Mülheim an der Ruhr, Germany

(e-mail: mailto:subhas@mpi-muelheim.mpg.de)

Rueping, M

Institute of Organic Chemistry and Chemical Biology,

Johann Wolfgang Goethe-Universität Frankfurt am Main,

Max-von-Laue-Straße 7, 60438 Frankfurt am Main, Germany

(e-mail: M.rueping@chemie.uni-frankfurt.de)

XIV List of Editors and Contributors

Selig, P.

Lehrstuhl für Organische Chemie I, Technical University Munich,Lichtenbergstr 4, 85747 Garching, Germany

Sugiono, E.

Institute of Organic Chemistry and Chemical Biology,

Johann Wolfgang Goethe-Universität Frankfurt am Main,

Max-von-Laue-Straße 7, 60438 Frankfurt am Main, Germany

Zeitler, K.

Institut für Organische Chemie, Universität Regensburg,

Universitätsstr 31, 93053 Regensburg, Germany

Ernst Schering Foundation Symposium Proceedings, Vol 2, pp 1–43

DOI 10.1007/2789_2008_084

© Springer-Verlag Berlin Heidelberg

Published Online: 30 April 2008

New Concepts for Organocatalysis

S.C Pan, B List( u )

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,

45470 Mülheim an der Ruhr, Germany

email: list@mpi-muelheim.mpg.de

1 Introduction: Organocatalysis 2

2 Enamine Catalysis 3

2.1 The Proline-Catalyzed Asymmetric Aldol Reaction: Scope, Mechanism and Consequences 5

2.2 Enamine Catalysis of Nucleophilic Addition Reactions 8

2.3 Enamine Catalysis of Nucleophilic Substitution Reactions 10

2.4 The Proline-Catalyzed Asymmetric Mannich Reactions 10

3 Brønsted Acid Catalysis 14

3.1 Catalytic Asymmetric Pictet–Spengler Reaction 15

3.2 Organocatalytic Asymmetric Reductive Amination 17

4 Iminium Catalysis 22

4.1 Organocatalytic Conjugate Reduction ofα,β-Unsaturated Aldehydes 24

5 Asymmetric Counteranion Directed Catalysis 26

5.1 Asymmetric Counteranion-Directed Catalysis: Application to Iminium Catalysis 28

6 Conclusions 33

References 34

Abstract Organocatalysis, catalysis with low-molecular weight catalysts in

which a metal is not part of the catalytic principle or the reaction substrate, can

be as efficient and selective as metal- or biocatalysis Important discoveries in this area include novel Lewis base-catalyzed enantioselective processes and, more recently, simple Brønsted acid organocatalysts that rival the efficiency

of traditional metal-based asymmetric Lewis acid-catalysts Contributions to

2 S.C Pan, B List

organocatalysis from our laboratories include several new and broadly ful concepts such as enamine catalysis and asymmetric counteranion-directedcatalysis Our laboratory has discovered the proline-catalyzed direct asymmet-ric intermolecular aldol reaction and introduced several other organocatalyticreactions

use-1 Introduction: Organocatalysis

When chemists make chiral compounds—molecules that behave likeobject and mirror image, such as amino acids, sugars, drugs, or nucleicacids—they like to use asymmetric catalysis, in which a chiral catalystselectively accelerates the reaction that leads to one mirror-image iso-mer, also called enantiomer For decades, the generally accepted viewhas been that there are two classes of efficient asymmetric catalysts: en-zymes and synthetic metal complexes (Nicolaou and Sorensen 1996).However, this view is currently being challenged, with purely organiccatalysts emerging as a third class of powerful asymmetric catalysts(Fig 1)

Most biological molecules are chiral and are synthesized in livingcells by enzymes using asymmetric catalysis Chemists also use en-zymes or even whole cells to synthesize chiral compounds and for a long

Fig 1 The three pillars of asymmetric catalysis: biocatalyis, metal catalysis and

organocatalysis

New Concepts for Organocatalysis 3

time, the perfect enantioselectivities often observed in enzymatic tions were considered beyond reach for non-biological catalysts Suchbiological catalysis is increasingly used on an industrial scale and isparticularly favored for hydrolytic reactions However, it became evi-dent that high levels of enantioselectivity can also be achieved usingsynthetic metal complexes as catalysts Transition metal catalysts areparticularly useful for asymmetric hydrogenations, but may leave pos-sibly toxic traces of heavy metals in the product

reac-In contrast, in organocatalysis, a purely organic and metal-free smallmolecule is used to catalyze a chemical reaction In addition to enrich-ing chemistry with another useful strategy for catalysis, this approachhas some important advantages Small organic molecule catalysts aregenerally stable and fairly easy to design and synthesize They are oftenbased on nontoxic compounds, such as sugars, peptides, or even aminoacids, and can easily be linked to a solid support, making them use-ful for industrial applications However, the property of organocatalystsmost attractive to organic chemists may be the simple fact that they areorganic molecules The interest in this field has increased spectacularly

in the last few years (Berkessel and Gröger 2005; List and Yang 2006).Organocatalysts can be broadly classified as Lewis bases, Lewis ac-ids, Brønsted bases, and Brønsted acids (for a review, see Seayad andList 2005) The corresponding (simplified) catalytic cycles are shown

in Scheme 1 Accordingly, Lewis base catalysts (B:) initiate the alytic cycle via nucleophilic addition to the substrate (S) The resultingcomplex undergoes a reaction and then releases the product (P) and thecatalyst for further turnover Lewis acid catalysts (A) activate nucle-ophilic substrates (S:) in a similar manner Brønsted base and acid cat-alytic cycles are initiated via a (partial) deprotonation or protonation,respectively

cat-2 Enamine Catalysis

Enamine catalysis involves a catalytically generated enamine diate that is formed via deprotonation of an iminium ion and that reactswith various electrophiles or undergoes pericyclic reactions The firstexample of asymmetric enamine catalysis is the Hajos–Parrish–Eder–