In Search of Beautiful Reactions: Organocatalysis
Beautiful Reaction- a reaction facilitated by an environmentally safe catalyst
in an environmentally safe solvent. Ideally, multiple reaction components are
assembled in a diastereo- and enantiospecific fashion to furnish stereochemically
complex products in a single step without by products.
Our interest in organocatalysis was piqued in 1997 when we initiated comparative
studies of aldolase antibodies with L-Proline, the well-known catalyst of the
intramolecular Hajos-Eder-Sauer-Wiechert reaction, an enantiogroup-differentiating
aldol cyclodehydration reaction. Evidence suggested that this intramolecular
proline-catalyzed reaction proceeds via an enamine reaction mechanism much like
our aldolase antibodies. Mechanistically then, catalysis with antibody aldolases
and the simple amino acid proline are very similar. We then demonstrated that
our aldolase antibodies were actually better catalysts than proline in the intramolecular
Hajos-Eder-Sauer-Wiechert reaction and in fact could catalyze the Michael step
as well as the aldol step of this annulation reaction. Empowered by our findings
with aldolase antibodies, we screened a wide variety of amino acids and chiral
amines with and without additives for catalysis of the U.V. active retro-aldol
reaction we developed to facilitate reaction screening with aldolase antibodies
under the premise that catalysts better than proline might be readily discovered.
In late 1998, after performing several hundreds of assays in order to best the
known catalyst proline, the technician assigned to this project, Tommy Bui*,
reported that despite his efforts proline and hydroxyproline remained most active
catalysts in the aldol reaction and organocatalysis with proline was reborn.
Proline provided us with the open active-site catalyst we had been searching
for in our promiscuous aldolase antibodies and it allowed us to catalyze reactions
that failed with aldolase antibodies due to substrate restrictions.
We have since shown that L-Proline and other chiral amines can be efficient
asymmetric catalysts of a variety of significant imine- and enamine-based reactions.
Studies from our laboratory and the contributions of others have advanced one
of the ultimate goals in organic chemistry, the catalytic asymmetric assembly
of simple and readily available precursor molecules into stereochemically complex
products under operationally simple and in some cases environmentally friendly
experimental protocols. One of the significant findings of these studies is
the development of catalysts that allow aldehydes, for the first time, to be
used efficiently as nucleophiles in a wide-variety of catalytic asymmetric reactions.
Previously, only Nature’s enzymes were thought capable of this chemical
feat. With future efforts, small organic catalysts may match some of Nature’s
other heretofore unmatched synthetic prowess and in doing so they may help explain
the development of complex chemical systems in the prebiotic world and provide
hints towards yet to be discovered mechanisms in extant biological systems.
We proposed and demonstrated for the first time that amino acids could catalyze
the direct synthesis of carbohydrates in optically active form. This theory
is now being investigated in laboratories around the world. Furthermore, we
believe that there exists a class of yet discovered Diels-Alderase enzymes that
utilize enamine and iminium catalysis. Using enamine and imine-based organocatalysis,
we have been able to directly synthesize a wide variety of α- and β-
amino acids, carbohydrates, amino sugars, Diels-Alder products, and lactams.
Stereochemically complex molecules can now be assembled using small molecules
in a manner analogous to nature’s enzymes. Indeed, we have now shown that
much of the synthetic chemistry of nature’s aldolase enzymes can be mimicked
using proline or other amine catalysts.
Organocatalysis is a creative and fast moving field of chemistry. A number of
postdoctoral fellows formerly associated with this laboratory and now in their
own laboratories have helped advance the field with the development of new reactions
and further elaborations of the reactions first developed here: Benjamin List,
Guofu Zhong, Shin-ichi Watanabe, Nobuyuki Mase, and Buchi Ramachary
Dhevalapally. This chemistry is also moving into the pharmaceutical industry
with the considerable contributions of Juan Betancort, Kandasamy Sakthivel,
Wolfgang Notz, Derek Steiner, Jeff Suri, Sreenivas Chowdari Naidu, and Rajeswari
Thayumanavan from this laboratory. Here at Scripps, we continue to enjoy a close
and highly productive collaboration with Fujie Tanaka.
We believe that Organocatalysis will provide many new and beautiful reactions
for some time to come.
For a recent review of this area see:
Notz, W.; Tanaka, F.; Barbas III, C.F. (2004) Enamine-based organocatalysis
with proline and diamines: The development of Direct Catalytic Asymmetric Aldol,
Mannich, Michael, and Diels-Alder Reactions. Accounts of Chemical Research,
37(8):580-591.