When developing a synthetic methodology, chemists generally optimize a single substrate and then explore the substrate scope of their method. This approach has led to innumerable and widely-used chemical reactions. However, it frequently provides methods that only work on model substrate-like compounds. Perhaps worse, reaction conditions that would enable the conversion of other substrates may be missed. We now show that a different approach, originally proposed by Kagan, in which a collection of structurally distinct substrates are evaluated in a single reaction vessel, can not only provide information on the substrate scope at a much earlier stage in methodology development, but even lead to a broadly applicable synthetic methodology. Using this multi-substrate screening approach, we have identified an efficient and stereoselective imidodiphosphorimidate organocatalyst for scalable Diels–Alder reactions of cyclopentadiene with different classes of α,β-unsaturated aldehydes.
An efficient organocatalyst for iminium-ion based asymmetric Diels-Alder (DA) reactions has been rationally designed. The most influential structure-activity relationships were determined experimentally, while DFT calculations and NMR studies provided further mechanistic insight. This knowledge guided an in silico screening of 62 different catalysts using an ONIOM(B3LYP/6-31G*:AM1) transition-state modeling, which showed good correlation between theory and experiment. The top-scored compound was easily synthesized from levoglucosenone, a biomass-derived chiral enone, and evaluated in the DA reaction between (E)-cinnamaldehyde and cyclopentadiene. In line with the computational finding, excellent results (up to 97% ee) were obtained. In addition, the catalyst could be easily recovered and reused with no loss in its catalytic activity.
We
have designed
and realized an efficient and operationally simple
single-flask synthesis of imidodiphosphate-based Brønsted acids.
The methodology proceeds
via
consecutive chloride
substitutions of hexachlorobisphosphazonium salts, providing rapid
access to imidodiphosphates (IDP), iminoimidodiphosphates (
i
IDP), and imidodiphosphorimidates (IDPi). These privileged
acid catalysts feature a broad acidity range (p
K
a
from ∼11 to <2 in MeCN) and a readily tunable confined
active site. Our approach enables access to previously elusive catalyst
scaffolds with particularly high structural confinement, one of which
catalyzes the first highly enantioselective
(>95:5 er) sulfoxidation of methyl
n
-propyl sulfide.
Furthermore, the methodology delivers a novel, rationally designed
super acidic catalyst motif, imidodiphosphorbis(iminosulfonylimino)imidate
(IDPii), the extreme reactivity of which exceeds commonly employed
super-Brønsted acids, such as trifluoromethanesulfonic acid.
The unique reactivity of one such IDPii catalyst has been demonstrated
in the first α-methylation of a silyl ketene acetal with methanol
as the electrophilic alkylating reagent.
The discovery of efficient organocatalysts
is generally carried
out by thorough experimental screening of different candidates. We
recently reported an efficient organocatalyst for iminium-ion-based
asymmetric Diels–Alder reactions following a rational design
approach. This result encouraged us to test this optimal catalyst
in the mechanistically related Friedel–Crafts alkylation of
indoles, but to our surprise, almost null enantioselectivity was observed.
The results did not significantly improve with structurally related
catalysts, and a totally unexpected facial selectivity inversion was
also noticed. Using DFT calculations by modeling the competing transition
structures with ONIOM, we could unravel the origins of those findings,
further employed to predict the most efficient catalyst for this new
transformation. The computational results were validated experimentally
(up to 92:8 er), providing another successful example of a general
strategy to accelerate catalyst development which still remains underexplored.
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