INSIGHTS | PERSPECTIVES
By Anita E. Mattson
Catalysis is an important strategy in the syntheses of societally relevant molecules; it is estimated that 90% of chemical processes rely on catalysts (1). Catalytic methods for the construction of chiral molecules, compounds that
can exist as mirror image isomers, are critical in the syntheses of bioactive molecules
such as pharmaceuticals and ag-rochemicals (2, 3). Mirror-image
isomers (enantiomers) can have
substantially diferent biological properties, so the selective
synthesis of just one enantiomer
is desirable. On page 761 of this
issue, Banik et al. (4) describe
an inventive catalytic approach
that combines hydrogen-bond
donors and Lewis acids to generate enhanced catalytic species
able to efect new types of enantioselective reactions.
There is a growing family
of small organic molecules,
referred to as hydrogen-bond
donors, that can catalyze enantioselective reactions through
noncovalent interactions (5). As
the name implies, a key design
element found in these catalysts
is a functional group, such as a
squaramide (6), thiourea (7), or
silanediol (8), that can recognize suitable
guest molecules through hydrogen-bonding
interactions. The molecular recognition
abilities of chiral hydrogen-bond donors allow for the catalysis of distinctive and useful reactions.
In a reactivity pattern often called asym-
metric anion-binding catalysis (9), an enan-
tiopure hydrogen-bond donor recognizes the
anionic component of an ion pair, thereby
generating a highly reactive cationic species
in a chiral environment. The strategic reac-
tion of a nucleophile with the cation of the
chiral ion pair then generates an enantio-
enriched product. In addition to the hydro-
gen-bonding interactions with an anion, a
complex network of rather weak noncovalent
interactions, such as general base activation,
and p-p and p-cation stacking, typically ex-
ists and supports the transition state that
leads to the major desired enantiomer.
Inherent to the noncovalent interactions
that enable the distinctive reactions of hydrogen-bond–donor catalysis are challenges
that can limit their widespread synthetic applications. For instance, noncovalent interactions are typically weak, so substrates are
often restricted to strong electrophiles with
carbon-heteroatom bonds that easily react.
This constraint prevents the realization of
the full potential of hydrogen-bond–donor
catalysis as a general solution in the synthesis of societally relevant target molecules,
such as medicinal agents and pesticides.
The hydrogen-bond–donor and Lewis
acid catalyst combination developed by
Banik et al. overcomes some of the limita-
tions facing conventional hydrogen-bond–
donor catalysis. In their work, the role of
the hydrogen-bond donor breaks from the
norm because it does not directly activate
the substrate alone. Instead, squaramide hy-
drogen-bond–donor activation of a second
catalyst, a silyl triflate, creates an enhanced
Lewis acid catalyst complex that can effect
enantioselective reactions of stable acetals
(see the figure). Importantly, Banik et al.
demonstrate that formation of the enhanced
catalyst complex is critical, in that neither
the squaramide nor silyl triflate alone could
efficiently activate stable acetals.
The generality of Banik et al.’s squaramide–
silyl triflate catalyst complexes to activate
stable acetals was demonstrated in reactions ranging from commonplace Mukaiyama aldol reactions to more demanding
The enhanced Lewis acid catalyst generated via the strategic
combination of a squaramide
and silyl triflate transforms the
role of enantioselective hydrogen-bond–donor catalysis. The
use of hydrogen-bond donors
should no longer be restricted
to conventional catalytic methods reliant on the direct activation of substrates. Instead, the
future of hydrogen-bond–donor
catalysis should include exploitation of hydrogen bonding and
anion recognition in the production of new catalytic species
to enable reactivity patterns
that are otherwise inaccessible.
This approach should inspire
the discovery of new catalyst
combinations and their associated methods
for complex molecule construction. j
1. American Chemistry Council, ICC-IEA-DECHEMA
Catalysis Roadmap (2015); www.americanchemistry.
2. C.A.Busacca,D.R.Fandrick, J.J.Song, C.H.Senanayke,
Adv. Synth. Catal. 353, 1825 (2011).
3. Chiral Pesticides: Stereoselectivity and Its Consequences,
vol. 1085 of the ACS Symposium Series, A. W. Garrison, J.
Gan, W. Li, Eds. (American Chemical Society, Columbus,
4. S. M. Banik, A. Levina, A. M. Hyde, E. N. Jacobsen, Science
358, 761 (2017).
5. A. G. Doyle, E. N. Jacobsen, Chem. Rev. 107, 5713 (2007).
6. J. P. Malerich, K. Harihara, V. H. Rawal, J.Am.Chem.Soc.
130, 14416 (2008).
7. M. S. Sigman, E. N. Jacobsen, J.Am.Chem.Soc. 120, 5315
8. A.G.Schafer,J.M. Wieting, T.J.Fisher, A.E.Mattson,
Angew. Chem. Int. Ed. 52, 11321 (2013).
9. K. Brak, E. N. Jacobsen, Ange w. Chem. Int. Ed .52, 534
Tricks for noncovalent catalysis
Hydrogen-bond donors activate Lewis acids to catalyze
Department of Chemistry, Worcester Polytechnic Institute,
100 Institute Road, Worcester, MA 01609, USA.
Squaramide structure (SQ)
H H MeO
tBu O O CF3
CF3 NH NH O
720 10 NOVEMBER 2017 • VOL 358 ISSUE 6364
Contacts enhance catalysts
Banik et al. show that a compound that makes hydrogen bonds to a Lewis acid
creates an active catalyst. An example of a cycloaddition reaction is depicted.
Tf, triflate; t-Bu, tert-butyl; Me, methyl; R, alkyl.