Lewis acid enhancement by
hydrogen-bond donors for
Steven M. Banik,* Anna Levina,* Alan M. Hyde, Eric N. Jacobsen†
Small-molecule dual hydrogen-bond (H-bond) donors such as ureas, thioureas, squaramides,
and guanidinium ions enjoy widespread use as effective catalysts for promoting a variety of
enantioselective reactions. However, these catalysts are only weakly acidic and therefore
require highly reactive electrophilic substrates to be effective. We introduce here a mode of
catalytic activity with chiral H-bond donors that enables enantioselective reactions of relatively
unreactive electrophiles. Squaramides are shown to interact with silyl triflates by binding the
triflate counterion to form a stable, yet highly Lewis acidic, complex. The silyl triflate-chiral
squaramide combination promotes the generation of oxocarbenium intermediates from acetal
substrates at low temperatures. Enantioselectivity in nucleophile additions to the cationic
intermediates is then controlled through a network of noncovalent interactions between the
squaramide catalyst and the oxocarbenium triflate.
Chiral hydrogen-bond (H-bond) donors can catalyze enantioselective nucleophile- electrophile addition reactions either by direct complexation with neutral electro- philes or by anion binding to generate chi-
ral ion-pair intermediates (Fig. 1A) (1, 2). However,
because of the generally weak Brønsted acidity
of the catalysts (3, 4), these approaches common-
ly require highly electrophilic substrates with
labile carbon-heteroatom (s or p) bonds (2). We
considered whether the anion-binding principle
could be applied in a fundamentally different
way to enhance the reactivity of Lewis acids such
as silyl triflates through association of a chiral
H-bond donor with the triflate. This strategy
could facilitate the generation of highly reactive
cationic intermediates from relatively stable pre-
cursors, while still enabling enantiocontrol through
noncovalent interactions with the chiral catalyst.
We report here the realization of this idea in the
discovery of cooperative reactivity between silyl
triflates and chiral squaramides and its applica-
tion to a series of enantioselective reactions in-
volving oxocarbenium ion intermediates.
Silyl triflates are readily available Lewis acids
with broad application in organic synthesis (5, 6).
The reactivity of these reagents is enhanced
through incorporation of more weakly coordinating anionic ligands such as disulfonimides, as
demonstrated initially by Ghosez in racemic Diels-Alder reactions (7–9). List and co-workers extended
this advance to enantioselective catalysis through
the design of chiral disulfonimide counteranions
that associate with the active silylium species (10, 11).
We envisaged an alternative approach wherein association of a chiral H-bond donor with the triflate
anion would generate a charge-separated complex
with enhanced Lewis acidity relative to silyl triflate
alone. Given the outstanding chiral induction properties of H-bond donors in reactions of ion-pair
intermediates, this approach would open the door
to a wide variety of enantioselective catalytic
Department of Chemistry and Chemical Biology, Harvard
University, Cambridge, MA 02138, USA.
*These authors contributed equally to this work.
†Corresponding author. Email: firstname.lastname@example.org
Fig. 1. Reactivity concept and reaction development. (A) Existing strategies for electrophile activation using chiral dual hydrogen-bond donor
catalysts and the approach explored in this study using anion binding to generate a reactive, cationic metal or metalloid center as a chiral ion pair.
(B) Proof-of-concept in the silyl triflate–promoted Mukaiyama aldol reaction of an acetal, with examples from optimization studies of the chiral
squaramide catalysts. (C) Representative examples of enantioselective alkylation reactions of acetals promoted by TBSOTf and catalyzed by 5e.