INSIGHT COMMENTARY NATURE|Vol 455|18 September 2008|doi:10.

1038/nature07367

The advent and development

of organocatalysis
David W. C. MacMillan

The use of small organic molecules as catalysts has been known for more than a century. But only in the past
decade has organocatalysis become a thriving area of general concepts and widely applicable asymmetric
reactions. Here I present my opinion on why the field of organocatalysis has blossomed so dramatically over
the past decade.

Organocatalysis, or the use of small organic molecules to catalyse organic new organocatalytic concepts. Instead, these articles focused only on
transformations, is a relatively new and popular field within the domain the individual transformations that had been accomplished. Because
of chiral molecule (or enantioselective) synthesis. Although chemical general lessons were not extrapolated from these reactions, the under-
transformations that use organic catalysts, or organocatalysts, have lying catalytic concepts were not applied to multiple reaction types. As
been documented sporadically over the past century, it was not until a result, chemists did not recognize that the use of small organocatalysts
the late 1990s that the field of organocatalysis was ‘born’, coalescing could be an overarching concept. One measure of this fact is that
around a small number of articles that inspired an explosion of research1. between 1960 and 1998, there were no review articles about the use of
Between 1998 and 2008, at least 1,500 manuscripts describing the use of organocatalysts. In addition, Dieter Seebach, an organic chemist of great
organocatalysts in more than 130 discrete reaction types were published standing, omitted organocatalysis from his vision for synthetic methods
(Fig. 1), a remarkable number given that there were no reports of such in 1990, clearly illustrating that it is not easy to predict the success of a
catalysts in the year 1995. It is now widely accepted that organocatalysis field that, at the time, does not exist.
is one of the main branches of enantioselective synthesis (the other, pre- In the late 1990s, however, things began to change when Yian Shi6,
viously accepted, branches being enzymatic catalysis and organometallic Scott Denmark7 and Dan Yang8, and their co-workers, demonstrated
catalysis; see page 314), and those who are involved in the synthesis of that enantiomerically pure ketones could be used to catalyse the enantio-
chiral molecules consider organocatalysis to be a fundamental tool in selective epoxidation of simple alkenes. Shortly afterwards, Eric Jacobsen9
their catalysis toolbox (see page 323). and Elias J. Corey10, and their co-workers, described the first examples of
In this Commentary, I present my opinion on how chemists arrived hydrogen-bonding catalysis, in an asymmetric Strecker reaction, and Scott
at this point. It is useful to look back and consider this development, not Miller and his co-workers11 introduced the concept of minimal peptides
least because it provides insight into how scientific communities can for the enantioselective kinetic resolution of alcohols. Although, collec-
seemingly bypass an important area of research for many decades and tively, this work did not conceptualize organocatalysis as a field of research,
then, at a given moment, embrace the same field with collective (and at it demonstrated for the first time that small organocatalysts could be used
times fervent) enthusiasm. I consider that three factors were crucial to to solve important problems in chemical synthesis. It was not until 2000,
the sudden birth and rapid growth of the field of organocatalysis: first, the however, that the field of organocatalysis was effectively launched, by two
conceptualization of the field; second, the advantages of organocatalytic publications that appeared almost simultaneously: one from Carlos Bar-
research; and, third, the advent of generic modes of catalyst activation, bas, Richard Lerner and Benjamin List12, on enamine catalysis; and the
induction and reactivity. other from my research group13, on iminium catalysis.
The work of Barbas, Lerner and List was significant because it showed
Conceptualization of the field of organocatalysis that the underlying mechanism of the Hajos–Parrish reaction could be
New synthetic methods are most likely to be encountered in the extended and applied to transformations that have a broader applicabil-
fields of biological and organometallic chemistry. ity (specifically, the intermolecular aldol reaction). Moreover, this work
Dieter Seebach (1990)2 showed that small organic molecules (such as proline) could catalyse the
same chemical reactions as much larger organic molecules (enzymes)
Why was organocatalysis so long overlooked as an area of research by by using similar mechanisms. Meanwhile, the report of iminium cata-
the chemical synthesis community? This question is difficult to answer lysis conceptualized ‘organocatalysis’ in three important ways: by delin-
in hindsight, given the now obvious nature of the concepts and cata- eating how organocatalysts could provide economic, environmental
lysts involved. However, one perspective worth considering is that it is and scientific benefits; by describing a general activation strategy for
impossible to overlook a field that does not yet exist. This might seem organocatalysis that could be applied to a broad range of reaction classes
cryptic, but it is similar to the idea that researchers cannot work on a (rather than simply allowing a single transformation); and by introduc-
problem that has not been identified. Between 1968 and 1997, there ing the term organocatalysis to the chemical literature. You might ask,
were only a few reports of the use of small organic molecules as cata- What’s in a name? But consider the success of the terms nanotechnology
lysts for asymmetric reactions (the Hajos–Parrish reaction probably and diversity-oriented synthesis at globally shifting the visibility and
being the most famous), but these chemical studies were viewed more perception of areas of research. The term organocatalysis provided a
as unique chemical reactions than as integral parts of a larger, intercon- strong identity and helped to unify a fledgling field, as well as attracting
nected field3–5. In these early publications, there was no emphasis on the the attention of the broader chemical synthesis community. At the last
potential benefits of using organocatalysts or on the demonstration of count, the word organocatalysis, or one of its derivatives, has been used
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600 Indeed, the increase in competition helped to accelerate the pace of

innovation and discovery, albeit perhaps at the expense of ‘elbow room’
for those in this popular field.
500
Some critics suggest that low turnover numbers might limit the poten-
Publications on organocatalysis

tial uses of organocatalysis for industrial applications, but this view is

400 simplistic and dogmatic. For any large-scale catalytic process, the most
salient considerations are cost and safety. Because organocatalysts are
often cheaper than metal-based catalysts, organocatalysts can be used in
300 larger quantities than metal-based ones for the same price. Moreover, it
is widely recognized in manufacturing that the removal of toxic catalyst-
200 related impurities from the waste stream can often have a larger financial
impact than the turnover number of the catalyst. Organocatalysts are
typically less toxic than metal-based catalysts, can be tolerated to a large
100 extent in waste streams and are more easily removed from waste streams,
again mitigating the cost of high catalyst loadings.
0
With respect to industrial applications, organocatalytic reactions are
1968 1972 1976 1980 1984 1988 1992 1996 2000 2004 of great use to medicinal chemists. These researchers are the largest
Year
body of industrial synthetic chemists in the world, and their techno-
logical needs often differ from those of chemists in manufacturing or
Figure 1 | An explosion of interest. The number of publications on the process development. Medicinal chemists need to find rapid, broadly
topic of organocatalysis has recently increased markedly. Data were applicable ways of constructing new candidate drugs for testing, so the
obtained by a search of the ISI Web of Knowledge in May 2008 for the most important considerations for a catalyst are its generality, conven-
keyword organocatalysis and its derivatives, as well as the keywords phase ience and robustness. Organocatalysts meet all of these operational
transfer, enamine and Hajos (to locate articles on this topic before the
requirements. Indeed, organocatalysts have already been taken up by
term organocatalysis was coined). This search is unlikely to have found all
publications on organocatalysis, and a conservative estimate is that more
some medicinal chemists in pursuit of therapeutic agents enriched for
than 2,000 manuscripts have been published on this topic so far. a particular enantiomer14.

Advent of generic modes of activation and induction

in more than 600 article titles and is the subject of more than 40,000 web Perhaps most crucial to the success of organocatalysis in the past decade
pages (based on a survey of the ISI Web of Knowledge and of web pages has been the invention or identification of generic modes of catalyst acti-
indexed by Google in May 2008). vation, induction and reactivity. A generic activation mode describes a
reactive species that can participate in many reaction types with consist-
Advantages of organocatalytic research ently high enantioselectivity (as opposed to one or two unique transfor-
Once the field of organocatalysis had been publicly defined, it grew mations). Such reactive species arise from the interaction of a single chiral
quickly. Such rapid adoption is possible only when a field offers real catalyst with a basic functional group (such as a ketone, aldehyde, alkene
advantages to the researchers who mine the area and to those who or imine) in a highly organized and predictable manner.
exploit the resultant technologies. In this case, the chemical syn- The value of generic activation modes is that, after they have been
thesis community quickly recognized the fundamental advantages established, it is relatively straightforward to use them as a platform
of organocatalysis, namely the ease and low cost of carrying out such for designing new enantioselective reactions. Indeed, most of the
reactions in the laboratory and the potential for new lines of academic 130 organocatalytic reactions that have been reported since 1998 are
thought and investigation. Before 1998, the state of the art in asymmet- founded directly on only five or six activation modes. The small number
ric catalysis involved metal-based chiral catalysts almost exclusively, and of activation modes in organocatalysis (and in catalysis in general) is
these catalysts allowed a wealth of oxidations, reductions, σ-bond inser- not surprising — when devising a new enantioselective reaction, it is far
tions, π-bond activations and Lewis-acid-catalysed reactions. Although easier to make use of a known activation mode than to invent a new one
the impact of metal-based catalysts on chemical synthesis cannot be (together with a new catalyst). Hence, the number of enantioselective
understated, some (but certainly not all) organometallic systems can catalytic reactions will always be much larger than the number of activa-
be expensive, toxic and/or sensitive to air and moisture. tion modes that underpin them.
The advent of organocatalysis brought the prospect of a complementary In many ways, this is beneficial to chemists, because it leads to the
mode of catalysis, with the potential for savings in cost, time and energy, an development of catalysts or catalyst families that are useful for a wide
easier experimental procedure, and reductions in chemical waste (Fig. 2). range of asymmetric reactions. At the same time, it is clear that discover-
These benefits arise from three factors. First, organic molecules are gen- ing new activation modes is important for all types of catalysis. In the
erally insensitive to oxygen and moisture in the atmosphere, so there is field of organocatalysis, iminium catalysis, reported in 2000, was the first
no need for special reaction vessels, storage containers and experimental
techniques, or for ultra-dry reagents and solvents. Second, a wide variety of • Stable in air and water
organic reagents — such as amino acids, carbohydrates and hydroxy acids N CO2H • Available from biological materials
H
— are naturally available from biological sources as single enantiomers. • Inexpensive and easy to prepare
Simple organocatalysts are therefore usually cheap to prepare and readily • Simple to use
t-Bu S
accessible in a range of quantities, suitable for small-scale reactions to H • Both enantioseries available
N
industrial-scale reactions. Third, small organic molecules are typically N
H
N
H • Non-toxic
O N
non-toxic and environmentally friendly, increasing the safety of catalysis R R
in both biological research and chemical research across all research set-
Figure 2 | Typical organocatalysts and the advantages of using
tings, including industry and academic institutions.
organocatalysts. l-Proline (top) is often used as an organocatalyst for
The combination of these factors substantially lowered the entry costs many reactions, notably for functionalizing carbonyl-containing molecules
for researchers who were interested in developing enantioselective cata- at the α-carbon. The mechanism involves the formation of a reactive
lysts. With no need for gloveboxes, inert gases, ultra-dry solvents or even enamine intermediate. Thioureas (bottom) catalyse several reactions by
high levels of experimental expertise, it is not surprising that the field forming hydrogen bonds with the substrate. The typical advantages of using
quickly became flooded with research groups from around the globe. organocatalysts are listed. R, alkyl; t-Bu, tert-butyl.

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Table 1 | Generic modes of activation commonly used in organocatalysis

Substrate Catalyst Activation mode Number Examples of new References
of new reaction variants
reactions
Enamine catalysis
HOMO activation 25 • Aldehyde–aldehyde First application: 1971, ref. 3
O
cross aldol coupling First use as a generic mode of
R • Intramolecular
N CO2H activation: 2000, ref. 13
Z H R Y N α-alkylation
X H • Mannich reaction
+ Z O
O • Michael reaction
X Y
• α-Amination
R = any organic chain or • α-Oxygenation
ring system • α-Halogenation
X = C, N, O, S • α-Sulphenylation
Y = generic organic atom
Z = alkyl, H
Hydrogen-bonding catalysis
LUMO activation 30 • Strecker reaction First application: 1996–1999,
X t-Bu S t-Bu • Mannich reaction refs 9–11
S
H H • Ketone cyanosilylation
R R' N N First use as a generic mode of
N N N N • Biginelli reaction activation: 2002, ref. 17
H H
X = O, NR O N O H H N • Pictet–Spengler reaction
R'' R'' X R'' R''
R, R', R'' = alkyl, aryl • Reductive amination
R R'

Nu

Iminium catalysis
LUMO activation 50 • Conjugate Friedel– First application and first use as
O O O
Crafts reaction a generic mode of activation:
N N • Ketone Diels–Alder 2000, ref. 14
H Ph reaction
Ph
N t-Bu N t-Bu
R H • exo-Selective Diels–
Alder reaction
R = alkyl, aryl Nu • Mukaiyama–Michael
R reaction
• Conjugate hydride
reduction
• Conjugate amination
• Conjugate oxygenation
• Conjugate sulphenylation
• Cyclopropanation
• Epoxidation, aziridination
SOMO catalysis
SOMO activation 4 • α-Allylation First application and first use as
O • α-Enolation a generic mode of activation:
O O
N N • α-Vinylation 2007, ref. 25
H • α-Heteroarylation
Ph Ph
R N t-Bu N t-Bu
H
R = alkyl, aryl Nu
R

Counterion catalysis
LUMO activation 2 • Acyl-Pictet–Spengler First application and first use as
t-Bu reaction a generic mode of activation:
Cl S t-Bu S
R' • Oxocarbenium addition 2007, ref. 28
N N
R X n-C5H11 N N
n-C5H11 N N reaction
H H
R'' O N O H H N
Cl
X= O, NR R''' R'''
R' X
R, R', R'', R''' = alkyl, aryl Nu R''
R

In HOMO activation, the energy of the highest-occupied molecular orbital (HOMO) is increased. In LUMO activation, the energy of the lowest-unoccupied molecular orbital (LUMO) is decreased. In SOMO activation,
an electron is located in a singly occupied molecular orbital (SOMO) to generate a highly reactive species that can participate in many reaction types. Nu, nucleophile; Ph, phenyl.

activation mode identified as being suitable for more than one reaction Enamine catalysis
type, a feature that was central to its design13. Enamine catalysis was also In 1971, there were two independent reports — one by Zoltan Hajos
demonstrated to be a generic activation mode by its application to the and David Parrish3, and another by Rudolf Weichert, Gerhard Sauer and
Mannich reaction in 2000 (ref. 15), and Jacobsen and Anna Wenzel were Ulrich Eder4 — of an enantioselective intramolecular aldol reaction
the first to demonstrate that hydrogen-bonding catalysis had multiple- that was catalysed by proline in the synthesis of the Wieland–Miescher
reaction utility, in 2002 (ref. 16). The activation modes discussed in this ketone. This extraordinary result was well received by the community,
section and described in Table 1 are representative of modes that have but the underlying activation mode was not exploited for other reactions
been invented or identified in the past decade. until more than 30 years later. It was in 2000, with the ingenious work of
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Barbas, Lerner and List — who used enamine catalysis to functionalize carbon–chlorine bonds of chloroamides and chloroacetals to generate
carbonyl-containing compounds at the α-carbon — that the broad a transient ion pair. The resultant anionic catalyst–chloride complex
applicability of this mode of activation became evident12. Since then, a functions as a chiral counterion, biasing the approach of nucleophiles to
tremendous amount of research has been directed towards identifying a single face of one enantiomer of the transient α-heteroatom-stabilized
new types of chiral enamine catalysts. cationic species. The initial results are remarkable in that forces acting
Mechanistically, enamine catalysis might be better described as through space, rather than through bonds, are sufficient to transfer
bifunctional catalysis because the amine-containing catalyst (proline stereochemical information from the catalyst to the substrate with high
in Table 1) typically interacts with a ketone substrate to form an enamine fidelity. Although this mode of activation is still in its infancy, it has
intermediate but simultaneously engages with an electrophilic reaction the potential to solve many persistent and outstanding problems in
partner through either hydrogen bonding or electrostatic attraction. This asymmetric catalysis.
mode of activation has now been used in a wide range of enantioselective
carbonyl α-functionalization processes17. The future
It is always a risk to predict what the future holds for any field, but several
Hydrogen-bonding catalysis aspects of organocatalysis will undoubtedly attract researchers’ attention.
In the early 1980s, researchers uncovered several catalytic asymmet- Tremendous efforts will continue to be directed towards the discovery
ric processes that suggested that the activation of a substrate and the and design of catalysts with better efficiency, new reactivities and greater
organization of the transition state could occur through well-defined turnover numbers. In addition, although SOMO catalysis and counterion
hydrogen-bonding interactions18–20. These reports were widely appreci- catalysis have been developed only recently, it is clear that at least ten new
ated; however, they were considered to be exceptions to the generally asymmetric transformations will arise from these modes of activation.
held idea that hydrogen bonding was insufficiently activating or direc- Moreover, given the substantial impact of new generic modes of activa-
tional for use in asymmetric catalysis. This reasoning was disproved tion, it is probable that many young and ambitious chemists will focus
by reports published in 1998 and 1999, when Jacobsen9 and Corey10 their research efforts on attaining this ideal. More specific challenges that
independently reported an asymmetric variant of the Strecker reaction are likely to be addressed include the organocatalytic activation of carbon–
that used well-defined hydrogen-bonding organocatalysts that activate hydrogen bonds and the catalysis of photoredox reactions. There will
imine electrophiles. Moreover, four years later, Jacobsen showed that also probably be further advances in the area of organocatalytic cascade
these thiourea catalysts could be used for other synthetic reactions16, reactions, in which activation modes are combined to provide powerful
launching the generic use of enantioselective hydrogen-bonding cata- transformations that generate complex molecules29,30. Although cascade
lysis. This powerful activation mode has become the foundation of a catalysis is rarely used at present, it is likely to become more prevalent for
large and dynamic area of research. More than 30 new asymmetric the synthesis of natural products and medicinal agents. Furthermore, it
reactions have been developed on the basis of this principle21. is probable that computational models will increasingly be used to aid
in not only the understanding of organocatalytic processes but also the
Iminium catalysis design of new organocatalysts (see page 309).
Iminium catalysis was the first organocatalytic activation mode to be But perhaps the most crucial area of research in the future will be the
designed (rather than discovered) and introduced as a general strategy identification of important transformations and new reactivities that are
for asymmetric organic synthesis. It is based on the capacity of chiral not available using other branches of catalysis. Given the huge growth and
amines to function as enantioselective catalysts for several transfor- impact of organocatalysis in the past decade, it will certainly be exciting
mations that traditionally use Lewis acid catalysts. The concept was to observe the development of the field over the next decade. ■
founded on the mechanistic hypothesis that the reversible formation of David W. C. MacMillan is at the Merck Center for Catalysis at Princeton
iminium ions from α,β-unsaturated aldehydes and chiral amines might University, 116 Frick Laboratory, Princeton University, Princeton,
emulate the equilibrium dynamics and π-orbital electronics that are New Jersey 08540, USA.
inherent to Lewis acid catalysis (that is, lowest-unoccupied molecular
orbital (LUMO)-lowering activation). With its tailor-made family of 1. Berkessel, A. & Groeger, H. Asymmetric Organocatalysis: from Biomimetic Concepts to
Applications in Asymmetric Synthesis (Wiley-VCH, 2005).
imidazolidinone catalysts, iminium catalysis is now used in more than 2. Seebach, D. Organic synthesis — where now? Angew. Chem. Int. Edn Engl. 29, 1320–1367
50 highly enantioselective protocols22, many of which have been devel- (1990).
oped by my research group and that of Karl Anker Jørgensen. 3. Hajos, Z. G. & Parrish, D. R. Asymmetric synthesis of optically active polycyclic organic
compounds. German patent DE 2102623 (1971).
4. Eder, U., Sauer, G. R. & Wiechert, R. Optically active 1,5–indanone and
SOMO catalysis 1,6–naphthalenedione derivatives. German patent DE 2014757 (1971).
Introduced by my research group in 2006, SOMO catalysis is based on 5. Hajos, Z. G. & Parrish, D. R. Asymmetric synthesis of bicyclic intermediates of natural
the idea that one-electron oxidation of an electron-rich enamine selec- product chemistry. J. Org. Chem. 39, 1615–1621 (1974).
6. Tu, Y., Wang, Z. & Shi, Y. An efficient asymmetric epoxidation for trans–olefins mediated by
tively generates a reactive radical cation with three π-electrons. The a fructose derived ketone. J. Am. Chem. Soc. 118, 9806–9807 (1996).
electrophilicity of the singly occupied molecular orbital (SOMO) of this 7. Denmark, S. E., Wu, Z., Crudden, C. & Matsuhashi, H. Catalytic epoxidation of alkenes with
intermediate allows it to react readily with a variety of weakly nucleophilic oxone. 2. Fluoro ketones. J. Org. Chem. 62, 8288–8289 (1997).
8. Yang, D. et al. A C2 symmetric chiral ketone for catalytic asymmetric epoxidation of
carbon-based ‘SOMOphiles’ at the α-carbon of the parent enamine, result- unfunctionalized olefins. J. Am. Chem. Soc. 118, 491–492 (1996).
ing in formal alkylation products23. Applying this principle in a catalytic 9. Sigman, M. & Jacobsen, E. N. Schiff base catalysts for the asymmetric Strecker reaction
system that uses chiral secondary amines and a suitable one-electron identified and optimized from parallel synthetic libraries. J. Am. Chem. Soc. 120, 4901–4902
(1998).
oxidant has been highly successful, opening up new avenues for catalysing 10. Corey, E. J. & Grogan, M. J. Enantioselective synthesis of α–amino nitriles from
the asymmetric α-functionalization of carbonyl-containing compounds. N-benzhydryl imines and HCN with a chiral bicyclic guanidine as catalyst. Org. Lett.
Although SOMO catalysis is one of the most recently discovered activa- 1, 157–160 (1999).
11. Miller, S. J. et al. Kinetic resolution of alcohols catalyzed by tripeptides containing the
tion modes, it has already yielded a series of enantioselective transforma- N–alkylimidazole substructure. J. Am. Chem. Soc. 120, 1629–1630 (1998).
tions that complement those produced by enamine catalysis24–26. 12. List, B., Lerner, R. A. & Barbas, C. F. III. Proline-catalyzed direct asymmetric aldol reactions.
J. Am. Chem. Soc. 122, 2395–2396 (2000).
13. Ahrendt, K. A., Borths, C. J. & MacMillan, D. W. C. New strategies for organic catalysis:
Counterion catalysis the first highly enantioselective organocatalytic Diels–Alder reaction. J. Am. Chem. Soc.
Jacobsen recently developed a conceptually novel form of organocatalytic 122, 4243–4244 (2000).
activation that directs highly enantioselective additions into transiently 14. King, H. D. et al. Enantioselective synthesis of a highly potent selective serotonin reuptake
generated N-acyl-iminium ions and oxocarbenium ions27,28. In this sys- inhibitor. An application of imidazolidinone catalysis to the alkylation of indoles with an
α,β-disubstituted α,β-unsaturated aldehyde. Org. Lett. 7, 3437–3440 (2005).
tem, chiral thiourea catalysts, which are known to form strong com- 15. List, B. The direct catalytic asymmetric three-component Mannich reaction. J. Am. Chem.
plexes with halide ions, electrostatically bind to, and ionize, the weak Soc. 122, 9336–9337 (2000).

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16. Wenzel, A. G. & Jacobsen, E. N. Asymmetric catalytic Mannich reactions catalyzed by occupied molecular orbital activation: the enantioselective α–enolation of aldehydes.
urea derivatives: enantioselective synthesis of β–aryl–β–amino acids. J. Am. Chem. Soc. J. Am. Chem. Soc. 129, 7004–7005 (2007).
124, 12964–12965 (2002). 26. Kim, H. & MacMillan, D. W. C. Enantioselective organo–SOMO catalysis: the α–vinylation
17. Mukherjee, S., Yang, J. W., Hoffmann, S. & List, B. Asymmetric enamine catalysis. of aldehydes. J. Am. Chem. Soc. 130, 398–399 (2008).
Chem. Rev. 107, 5471–5569 (2007). 27. Raheem, I., Thiara, P. S., Peterson, E. A. & Jacobsen, E. N. Enantioselective Pictet–Spengler-
18. Hiemstra, H. & Wynberg, H. Addition of aromatic thiols to conjugated cycloalkenones, type cyclizations of hydroxylactams: H-bond donor catalysis by anion binding. J. Am. Chem.
catalyzed by chrial β–hydroxy amines. A mechanistic study on homogeneous catalytic Soc. 129, 13404–13405 (2007).
asymmetric synthesis. J. Am. Chem. Soc. 103, 417–430 (1981). 28. Reisman, S. E., Doyle, A. G. & Jacobsen, E. N. Enantioselective thiourea-catalyzed additions
19. Oku, J. I. & Inoue, S. Asymmetric cyanohydrin synthesis catalyzed by a synthetic cyclic to oxocarbenium ions. J. Am. Chem. Soc. 130, 7198–7199 (2008).
dipeptide. J. Chem. Soc. Chem. Commun. 229–230 (1981). 29. Huang, Y., Walji, A. M., Larsen, C. H. & MacMillan, D. W. C. Enantioselective organo-
20. Dolling, U. H., Davis, P. & Grabowski, E. J. J. Efficient catalytic asymmetric alkylations. cascade catalysis. J. Am. Chem. Soc. 127, 15051–15053 (2005).
1. Enantioselective synthesis of (+)–indacrinone via chiral phase-transfer catalysis. 30. Enders, D., Grondal, C. & Huttl, M. R. M. Asymmetric organocatalytic domino reactions.
J. Am. Chem. Soc. 106, 446–447 (1984). Angew. Chem. Int. Edn Engl. 46, 1570–1581 (2007).
21. Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis.
Chem. Rev. 107, 5713–5743 (2007). Acknowledgements I thank the National Institute of General Medical Sciences
22. Lelais, G. & MacMillan, D. W. C. Modern strategies in organic catalysis: the advent and (grant number R01 GM078201-01-01) for financial support, and Merck Research
development of iminium activation. Aldrichim. Acta 39, 79–87 (2006). Laboratories and Bristol-Myers Squibb for gifts. I also thank H. Kim, R. Knowles,
23. Narasaka, K., Okauchi, T., Tanaka, T. & Murakami, M. Generation of cation radicals from D. Carerra and J. Van Humbeck for their help in the preparation of the manuscript.
enamines and their reactions with olefins. Chem. Lett. 92, 2099–2102 (1992).
24. Beeson, T. D., Mastracchio, A., Hong, J., Ashton, K. & MacMillan, D. W. C. Author Information Reprints and permissions information is available at
Enantioselective organocatalysis using SOMO activation. Science, 316, 582–585 (2007). www.nature.com/reprints. The author declares no competing financial interests.
25. Jang, H., Hong, J. & MacMillan, D. W. C. Enantioselective organocatalytic singly Correspondence should be addressed to the author ([email protected]).

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