Volume 107, Number 12

Introduction: Organocatalysis
The catalysis with small organic molecules, where an
inorganic element is not part of the active principle, has
become a highly dynamic area in chemical research. Re-
markably though, while several special issues in various
journals, book chapters, and even entire monographs have
appeared on this topic in recent years, not too long ago the
field essentially didn’t even exist. For example, in the late
1990s, Sorensen and Nicolaou in their brilliant book Classics
in Total Synthesis defined asymmetric catalysis by rather
accurately (at the time!) stating that “In a catalytic asym-
metric reaction, a small amount of an enantiomerically pure
catalyst, either an enzyme or a synthetic, soluble transition
metal complex, is used to produce large quantities of an
optically active compound from a precursor that may be
chiral or achiral.” Benjamin List was born in 1968 in Frankfurt, Germany. He graduated
This view has been significantly altered, and it is clear by from Freie University Berlin (1993) and received his Ph.D. (1997) from
now that modern asymmetric catalysis is built on three rather the University of Frankfurt (Mulzer). After postdoctoral studies (1997−
than two pillars, namely biocatalysis, metal catalysis, and 1998) as a Feodor Lynen Fellow of the Alexander von Humboldt foundation
at The Scripps Research Institute (Lerner), he became a Tenure Track
organocatalysis. In light of this, it is quite remarkable that Assistant Professor there in January 1999. Subsequently, he developed
organic chemists had long ignored the fact that the very first the first proline-catalyzed asymmetric intermolecular aldol, Mannich,
catalysts they used in ancient times were purely organic Michael, and R-amination reactions and received a grant on Asymmetric
molecules such as acetaldehyde (Liebig in 1859). As organic Aminocatalysis from the National Institutes of Health. He moved to the
molecules readily react with each other, why did we disregard Max-Planck-Institut für Kohlenforschung in 2003 as an associate professor
(2003−2005) and currently is a director (full professor) there and an
these compounds as catalysts and rather relied on the honorary professor at the University of Cologne. His research interests
assistance of biologists and inorganic chemists to provide are new catalysis concepts, bioorganic chemistry, and natural product
enzymes or explain the foreign world of d-orbitals to us? synthesis. He has received several awards, including the Carl-Duisberg-
Why did we not expect catalytic competence from organic Memorial Award of the German Chemical Society (2003), the Degussa
moleculessexactly those compounds we can truly design, Prize for Chiral Chemistry (2004), the Lecturer’s Award of the Endowment
of the Chemical Industry (2004), the Lieseberg-Prize of the University of
make, and know most about? Heidelberg (2004), The Society of Synthetic Chemistry, Japan Lectureship
While this thematic issue may not provide an answer to Award (2005), the Novartis Young Investigator Award (2005), the OBC-
these intriguing questions, it will hopefully give an overview Lecture Award (2007), and, most recently, the AstraZeneca Award in
of the area of organocatalysis and provide a more logical Organic Chemistry. He is currently an editor of Synfacts and coordinates
the DFG-priority program “Organocatalysis”.
structure to the field. There are essentially four types of
organocatalysts, Lewis bases, Lewis acids, Brønsted bases,
and Brønsted acids. These catalysts initiate their catalytic I have the good fortune of being the Guest Editor for this
cycles by either providing or removing electrons or protons thematic issue, and have organized it into five units, one on
from a substrate or a transition state. Organocatalysis is each of the four types of catalysis modes above, and a fifth
dominated by Lewis base catalysts such as amines and on miscellaneous aspects of organocatalysis. Gratifyingly,
carbenes, while Lewis acids such as carbonyl compounds several of the leaders within these areas have contributed
are rarely used. A relatively new concept is the use of chiral articles, and I would like to take this opportunity to thank
organic Brønsted acid catalysts. This area is likely to grow them for their excellent contributions as well as John Gladysz
strongly and is expected (at least by the writer) to ultimately and his reviewers for their heroic efforts of assuring high
deliver extremely active catalysts that rival the efficiency of quality. Less fortunately though, not all key elements of
enzymes and that of the few superactive chiral transition organocatalysis could be included, which is mostly due to
metal complexes, such as Noyori’s hydrogenation catalysts an incompatible time schedule of potential authors with the
or certain Suzuki reaction catalysts. publisher. For example, a treatment of ketone-catalyzed
10.1021/cr078412e CCC: $65.00 © 2007 American Chemical Society
Published on Web 12/12/2007
5414 Chemical Reviews, 2007, Vol. 107, No. 12 Editorial

epoxidations is missing. This area forms one-half of Lewis

acid organocatalysis, which leaves this topic solely (and
arguably) to phase transfer catalysis. Also, the reader will
notice that some authors have taken the liberty to expand
certain areas beyond organocatalysis to include other themes
such as biocatalysis and transition metal catalysis, and even
noncatalytic reactions. This is certainly not due to an unclear
definition of what organocatalysis is, but rather is based on
the opinion of these authors that their topics should be viewed
from a broader angle.
The first five articles out of the twelve in this issue deal
with Lewis base catalysis, once again illustrating the
dominance of this area in organocatalysis. Anniina Erkkilä,
Inkeri Majander, and Petri Pihko start the issue with a
thorough treatise on one of the most powerful and general
strategies of organocatalysis, “Iminium Catalysis”, introduced Figure 1. Number of publications using the term “organocatalysis”
by David MacMillan and his group in 2000. This review in the title or abstract since the year 2000: b, from SciFinder as
also includes a highly readable section on the rich history of November 21, 2007; O, predicted.
of this interesting activation mode.
Our article (by Santanu Mukherjee, Jung Woon Yang, subject into a broader context by including many non-
Sebastian Hoffmann, and Benjamin List) on “Asymmetric organocatalytic processes.
Enamine Catalysis” follows. During the preparation of this The subsequent two articles deal with Brønsted acid
review, we realized how the enamine catalysis concept that catalysis. This area has grown significantly since the late
we had originally proposed in 2000 has developed into a 1990s, when, by serendipity, Eric Jacobsen and his team
powerful strategy that has delivered an impressive amount identified an exceptionally active and enantioselective H-
of highly useful, general, and enantioselective reactions. The bonding catalyst of the Strecker reaction. In their review,
development of enamine catalysis, as well as that of iminium Abigail G. Doyle and Eric N. Jacobsen have also decided to
catalysis, has not only been inspired by the Hajos-Parrish- take a broader approach to the area of “Small-Molecule
Eder-Sauer-Wiechert reaction but has also been “cata- H-Bond Donors in Asymmetric Catalysis”. Some reactions
lyzed” by the creation of aldolase catalytic antibodies in the are included that may also be classified differently, such as
laboratories of Lerner and his team (Barbas, Reymond). the proline-catalyzed aldol reaction, and are covered from a
different perspective in other articles in this issue.
Continuing with the theme of nitrogen Lewis bases,
This seems to point to a general challenge in classifying
valuable contributions by Ryan P. Wurz on asymmetric
organocatalysts: Often there is little knowledge of a given
catalysis with DMAP analogues and by Matthew J. Gaunt reaction mechanism and the exact mode of activation is
and Carin C. C. Johansson on organocatalysis via ammonium unknown. Even more complicating is the fact that many
enolates follow. The fifth article in this series by Dieter organocatalysts are bifunctional. For example, a urea catalyst
Enders, Oliver Niemeier, and Alexander Henseler discusses that incorporates an amine may be described either as an
“Organocatalysis by N-Heterocyclic Carbenes”, which for H-bonding donor catalyst or as a Brønsted base catalyst.
a long period only meant the benzoin condensation and Accordingly, such catalysts can, in principle, be treated in
Stetter reaction. This area has grown enormously, not the either of the two units.
least with the recent discovery of an a3-d3-type umpolung
Next, Takahiko Akiyama describes the use of “Stronger
introduced independently by Glorius and Bode.
Brønsted Acids” in asymmetric organocatalysis. In contrast
Normally, the next logical article in the unit on Lewis base to H-bond donor catalysts, which form hydrogen bonds to a
catalysis would be Varinder Aggarwal and his coauthors’ transition state, these are strong enough acids to protonate
timely discussion on “Chalcogenides as Organocatalysts”. the substrate of a reaction, forming ion pairs as intermediates.
However, as this review discusses very little “true” organo- The area has grown quite a bit since its invention by the
catalyis (using the above definition) but is obviously related author as well as independently by Terada and his group in
to the general topic, it has been moved into the fifth unit on 2004.
miscellaneous organocatalysis aspects. The last unit deals with miscellaneous aspects of organo-
An article on Lewis acid organocatalysis by Takuya catalysis, such as peptide catalysts. This area is mostly based
Hashimoto and Keiji Maruoka follows, in which they outline on the work of Miller et al. Elizabeth A. Colby Davie, Steven
recent developments in phase transfer catalysis (PTC). The M. Mennen, Yingju Xu, and Scott J. Miller, in their review,
authors discuss highly useful and active catalysts based on deal with catalysts that are right in-between the worlds of
quaternary ammonium salts. Please note that some organo- small organic molecules and proteins.
catalysis purists have argued that as phase transfer catalysis Nahrain E. Kamber, Wonhee Jeong, Robert M. Waymouth,
typically involves metal enolates, it should not be considered Russell C. Pratt, Bas G. G. Lohmeijer, and James L. Hedrick
organocatalysis. Because purely organic examples of PTC describe the increasing use of organocatalysis in polymeri-
have been reported, the area is included here nonetheless. zation chemistry in their article on “Organocatalytic Ring-
Another single-article-unit on Brønsted base catalysis Opening Polymerization”.
follows, in which Iuliana Atodiresei, Ingo Schiffers, and The thematic issue closes with Eoghan M. McGarrigle,
Carsten Bolm discuss “Stereoselective Anhydride Openings”. Eddie L. Myers, Ona Illa, Michael A. Shaw, Samantha L.
Although this area is clearly dominated by cinchona alkaloid- Riches, and Varinder K. Aggarwal’s treatment of “Chaco-
catalyzed alcoholyses of anhydrides, the authors put the genides as Organocatalysts”. This article describes several
Editorial Chemical Reviews, 2007, Vol. 107, No. 12 5415

interesting reactions that mostly lead to three-membered rings academia. I predict that the coming two decades will bridge
and that typically combine organocatalysis and metal ca- the gap between the current academic excitement on the one
talysis. hand and the industrial realities on the other. I can hardly
As illustrated by the citation statistics in the figure, it is wait to read the Chemical ReViews thematic issue on Organo-
obvious that organocatalysis has grown quite dramatically catalysis to be published in the year 2027, reporting the
in recent years. Yet, the field should certainly not be spectacular advancements that will surely be made by then!
considered “mature”, maybe not even “adolescent”. Several
areas are yet completely unexplored, and new concepts will
surely arise within the more established ones. Also, there Benjamin List
are already a number of organocatalytic reactions being used
in the pharmaceutical and chemical industries. Yet, the area Max-Planck-Institut für Kohlenforschung
is clearly not as “mainstream” in industry as it already is in CR078412E