Table Of ContentEnantioselection in
Asymmetric Catalysis
Enantioselection in
Asymmetric Catalysis
Ilya D. Gridnev
Pavel A. Dub
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2017 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Printed on acid-free paper
Version Date: 20160802
International Standard Book Number-13: 978-1-4987-2654-2 (Hardback)
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts
have been made to publish reliable data and information, but the author and publisher cannot assume
responsibility for the validity of all materials or the consequences of their use. The authors and publishers
have attempted to trace the copyright holders of all material reproduced in this publication and apologize to
copyright holders if permission to publish in this form has not been obtained. If any copyright material has
not been acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmit-
ted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented,
including photocopying, microfilming, and recording, or in any information storage or retrieval system,
without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.
com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood
Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and
registration for a variety of users. For organizations that have been granted a photocopy license by the CCC,
a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used
only for identification and explanation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data
Names: Gridnev, Ilya D., 1963- | Dub, Pavel A.
Title: Enantioselection in asymmetric catalysis / Ilya D. Gridnev and Pavel A.
Dub.
Description: Boca Raton : CRC Press, 2017. | Includes bibliographical
references and index.
Identifiers: LCCN 2016032429 | ISBN 9781498726542 (hardcover : alk. paper)
Subjects: LCSH: Enantioselective catalysis. | Catalysis. | Asymmetric
synthesis.
Classification: LCC QD505 .G7545 2017 | DDC 541/.395--dc23
LC record available at https://lccn.loc.gov/2016032429
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
Contents
Introduction .......................................................................................................ix
Authors ...............................................................................................................xi
Chapter 1 Transition metal-catalyzed hydrogenation ............................1
1.1 Rh-catalyzed asymmetric hydrogenation of activated olefins .........1
1.1.1 Overview ....................................................................................1
1.1.2 Asymmetric hydrogenation catalyzed
by Rh–diphosphine ligands .....................................................1
1.1.2.1 Resting state of the catalytic cycle:
Formation of the catalyst–substrate complexes ....1
1.1.2.2 Activation of H .........................................................8
2
1.1.2.3 Formation of solvate dihydrides ...........................12
1.1.2.4 Oxidative addition to chelate
catalyst–substrate complexes ................................15
1.1.2.5 Reactions of solvate dihydrides with
prochiral substrates ................................................22
1.1.2.6 Catalytic cycle and enantioselective step ............33
1.1.2.7 Process of enantioselection ....................................37
1.1.2.8 Sense of enantioselection and the relative
size of substituents..................................................54
1.1.3 Catalysis with rhodium complexes of monophosphines ...62
1.1.4 Conclusions ..............................................................................65
1.2 Ru-catalyzed asymmetric hydrogenation and transfer
hydrogenation of ketones .....................................................................68
1.2.1 Overview ..................................................................................68
1.2.2 A brief critical overview of experimental and
computational techniques used in the early
mechanistic studies of 1 and 2 ...............................................71
1.2.2.1 The characteristic time and sensitivity of
NMR spectroscopy .................................................71
1.2.2.2 Kinetics .....................................................................71
1.2.2.3 Computations in the gas-phase ............................73
1.2.3 Progress of the reaction mechanism with 1 and 2 ..............74
v
vi Contents
1.2.4 The origin of the enantioselectivity ......................................85
1.2.5 Unresolved problems ..............................................................89
1.2.5.1 Reaction mechanism ..............................................89
1.2.5.2 Enantioselectivity ...................................................92
1.3 Ir-catalyzed asymmetric hydrogenation of
C=C and C=N bonds ............................................................................94
1.3.1 Overview .............................................................................94
1.3.2 Catalytic cycle and intermediates .........................................94
1.3.3 Mechanism of enantioselection .............................................97
1.3.3.1 Simple olefins ..........................................................98
1.3.3.2 Imines .....................................................................100
1.3.3.3 Heterocycles ...........................................................101
1.3.4 Conclusion ..........................................................................104
1.4 Pd-catalyzed asymmetric hydrogenation of indoles ......................104
1.4.1 Overview ................................................................................104
1.4.2 Catalytic cycle.........................................................................105
1.4.3 Enantioselectivity ..................................................................106
References ........................................................................................................108
Chapter 2 Other enantioselective reactions catalyzed by
transition metals .....................................................................133
2.1 Enantioselective reactions catalyzed by bifunctional Ru and
Ir complexes ..........................................................................................133
2.1.1 Mechanism of the Michael addition catalyzed by
bifunctional Ru catalysts ......................................................133
2.1.2 Mechanism of C–C and C–N bond forming reactions
catalyzed by bifunctional Ir catalysts .................................135
2.2 Rh-catalyzed stereoselective isomerization of
tert-cyclobutanols into chiral indanoles ...........................................143
2.2.1 Overview ................................................................................143
2.2.2 Catalytic cycle.........................................................................144
2.3 Os-catalyzed asymmetric dihydroxylation
(Sharpless reaction) ........................................................................147
2.3.1 Overview ................................................................................147
2.3.2 Catalytic cycle.........................................................................149
2.3.3 Enantioselectivity ..................................................................149
2.4 Pd- and Rh-catalyzed conjugate additions of arylboronic acids
to enones and nitrostyrenes (Hayashi−Miyaura reaction) ............152
2.4.1 Overview ................................................................................152
2.4.2 Catalytic cycle.........................................................................152
2.4.3 Catalytic cycle (M = Rh, Scheme 2.12) ................................154
2.4.4 Origin of enantioselectivity (M = Pd) .................................155
2.4.5 Origin of enantioselectivity (M = Rh) ................................157
Contents vii
2.5 Rh-catalyzed asymmetric hydroboration of vinylarenes ..............158
2.5.1 Overview ................................................................................158
2.5.2 Catalytic cycle.........................................................................160
2.5.3 Enantioselectivity ...................................................................161
2.6 Mechanism of autoamplifying Soai reaction ..................................164
2.6.1 Introduction ............................................................................164
2.6.2 Studies of the reaction pool of Soai reaction .....................166
2.6.3 Structure of the catalyst and computations of the
catalytic cycle of Soai reaction .............................................168
References ........................................................................................................172
Chapter 3 Mechanism of enantioselection in organocatalytic
reactions ....................................................................................183
3.1 Phosphoric acids ..................................................................................183
3.1.1 Asymmetric allylboration ....................................................183
3.1.2 Kinetic resolution in Robinson-type cyclization...............184
3.1.3 Friedel–Crafts alkylation of indoles with nitroalkenes .......185
3.1.4 Petasis–Ferrier-type rearrangement ...................................188
3.1.5 Enantioselective indole aza-Claisen rearrangement ........190
3.1.6 Asymmetric thiocarboxylysis of meso-epoxide ................190
3.1.7 Asymmetric sulfoxidation reaction ....................................192
3.2 Cinchona alkaloids ..............................................................................192
3.2.1 Asymmetric olefin isomerization ........................................194
3.2.2 Friedel–Crafts alkylation of indoles with
α,β-unsaturated ketones .......................................................195
3.2.3 Conjugate addition of dimethyl malonate to
β-nitrostyrene .........................................................................198
3.2.4 Fluorination of cyclic ketones ..............................................199
3.2.5 Phase-transfer-catalyzed alkylation reaction ....................200
3.3 Urea and thiourea-based catalysts ....................................................201
3.3.1 Catalytic Strecker reaction ...................................................202
3.3.2 Michael addition reactions ...................................................203
3.3.3 Enantioselective decarboxylative protonation ..................205
3.3.4 Henry reaction .......................................................................207
3.3.5 α-Hydroxylation of β-ketoesters ..........................................209
3.4 N-Protonated chiral oxazaborolidine ...............................................212
3.4.1 C−C insertion reaction ..........................................................212
viii Contents
3.5 FLP-catalyzed asymmetric hydrogenation of imines and
enamines ................................................................................................214
3.5.1 Overview .................................................................................214
3.5.2 Catalytic cycle..........................................................................216
3.5.3 Enantioselectivity ...................................................................216
References ........................................................................................................218
Conclusions .....................................................................................................225
Index ................................................................................................................229
Introduction
The idea of writing this book came when the authors were finalizing
their long-term studies of the mechanisms of asymmetric Rh-catalyzed
hydrogenation of activated olefins (IDG) and Ru-catalyzed hydrogena-
tion and transfer hydrogenation of aromatic ketones (PAD). Both fields
have attracted a considerable interest from researchers due to the utmost
effectiveness and extremely high levels of enantioselectivity that were
achieved in certain reactions of this type. This supports the attempts to
uncover the real mechanism of the generation of chirality, because the
observation of optical yields of over 99% ee suggests it would be easier to
locate a real catalytic pathway among the numerous possibilities.
Nevertheless, during their experimental and computational studies,
the authors became convinced that, even in the case of extremely high
optical yields, it is not easy to establish reliably the actual pathways taken
in the multistep catalytic cycles and elucidate the factors important for the
effective generation of chirality.
There are several reasons for these complications, but all of them
come from the same origin: the multistep character of the catalytic cycles.
It means, for example, that several stages of a chiral catalytic cycle can be
enantioselective. Therefore, we can compute or even observe experimen-
tally a high enantioselectivity for a certain step of the catalytic cycle but
still cannot be completely confident if it is actually this step that is respon-
sible for the overall chirality of the product.
Practically it means that the whole network of possible catalytic path-
ways that may be converging and/or may contain bifurcation points must
be computed before a reliable decision on the nature of the enantioselec-
tive step can be made. This, in turn, requires accurate knowledge of all
possible experimental data on the relative stabilities of the intermediates,
structure of the resting state, kinetics, etc., to calibrate and control the
computational results.
In other words, the elucidation of the mechanism of enantioselection
in an asymmetric catalytic reaction is not an easy and straightforward
task; it requires extensive experimental and computational studies. The
first two reactions discussed in this book are evidently exceptional with
ix
