Unified Approach to Imidodiphosphate-Type Brønsted Acids with Tunable Confinement and Acidity.

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 (iIDP), and imidodiphosphorimidates (IDPi). These privileged acid catalysts feature a broad acidity range (pKa 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.

Re-Engineering Organocatalysts for Asymmetric Friedel-Crafts Alkylation of Indoles through Computational Studies.

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.

Mechanistic insight into the acid-catalyzed isomerization of biomass-derived polysubstituted pyrrolidines: an experimental and DFT study.

The 1,3-dipolar cycloaddition reactions of azomethine ylides is one of the preferred methods for the synthesis of polysubstituted pyrrolidines. The use of chiral dipolarophiles derived from carbohydrates yields enantiomerically pure pyrrolidines, usually in good to excellent endo selectivities, along with other minor stereoisomers. Recently, we found an unusual isomerization event that allowed the isolation of useful pyrrolidines with relative stereochemistries difficult to obtain otherwise. Although a simple and efficient protocol to promote these transformations was developed, the mechanism was not fully unravelled. Herein, after a combination of experimental, spectroscopic and computational studies (using DFT methods) we propose that this isomerization event takes place through a retro-Mannich//Mannich cascade, via the formation of an iminium ion with E geometry.

Joint Experimental, in Silico, and NMR Studies toward the Rational Design of Iminium-Based Organocatalyst Derived from Renewable Sources.

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.