Over the last decade, with the surge in the development of organocatalysis, many processes involving chiral ion pairs have emerged as powerful tools in the design of new efficient organocatalysts. This tutorial review focuses on the recent evolutions of these organocatalytic systems in which both anionic and cationic parts are working in a cooperative fashion in order to develop unique catalytic processes which outperform the existing approaches. In this respect, chiral ion pairs opened new avenues in the design of bifunctional organocatalysts by means of combinatorial approaches.

A chiral quaternary ammonium amide was generated in situ from N,O-bis(trimethylsilyl)-A C H T U N G T R E N N U N G acetamide (BSA) as non-nucleophilic Brønsted base precursor and the combination of chiral quaternary ammonium halide/sodium aryloxide as chiral Lewis base. This system was applied to an anti-selective organocatalytic direct vinylogous aldol (ODVA) reaction of (5H)-furan-2-one derivatives with aldehydes. Several 5-(1'-hydroxy)-g-butenolides were obtained in good diastereomeric ratios (up to 95/5) and excellent enantioselectivities (up to 94%) with both aliphatic or (hetero)aromatic aldehydes, so providing a rare example of general and efficient conditions for the ODVA reaction.

No abstract

International audienc

In the present work, enantioselective protonation of silyl enol ethers is reported by means of a variety of chiral nitrogen bases as catalysts, mainly derived from cinchona alkaloids, in the presence of various protic nucleophiles as proton source. A detailed study of the most relevant reaction parameters is disclosed allowing high enantioselectivities of up to 92% ee with excellent yields to be achieved under mild and eco-friendly conditions. The synthetic utility of this organocatalytic protonation was demonstrated during the preparation of two homoisoflavones 4a and 4b, isolated from Chlorophytum Inornatum and Scilla Nervosa, which were obtained with 81% and 78% ee, respectively.

Am ethodology allowing the one-pot preparation of difluorinateda ldols directly from Ruppert-Prakash reagent, acyltrimethylsilanes and aldehydes is reported. Thep rocess,i nitiated by ac atalytic amount of an ammonium salt, involves the addition of (trifluoromethyl)trimethylsilane to the acylsilane,f ollowed by aB rook rearrangement and elimination of af luoride anion that promotes the subsequent aldol reaction. An efficient racemic reaction catalyzed by tetrabutylammonium difluorotriphenylsilicate is described, as wellasour first efforts towards an asymmetric version.Keywords: aldol reaction; Brook rearrangement; fluorine;organocatalysis While long ignored by organic and medicinal chemists,f luorinated molecules have increasingly attracted their attention since half ac entury.T he ever-growing number of fluorinated drugs anda grochemicals released on the market every year reflectst his situation.[1] This popularity arises from the uniquep roperties of the fluorine atom ando ft he C À Fb ond. The fluorine atom is the second smallest (van derW aals radius is 1.47 ) of the periodic table and exhibitst he strongest electronegativity (4.0 on the Pauling scale). TheC À Fb ond is consequently short( 1.35 ) andh as av ery high dissociation energy of 105.4 kcalmol À1 . [2] Thanks to these properties,t he introduction of fluorine onto ab ioactive molecule haso ften major consequenceso ni ts pharmacodynamico rp harmacokinetic properties.I ndeed, the presence of af luorine atom or af luorinated group in the appropriate position can improvethe binding of am olecule with areceptor, increase its lipophilicity,m odulatei ts pK a or inhibit its metabolic degradation.[3] Then umber of fluorinated drugs hasc onsequently increased, as wella st he need for methodologies that enable the efficientp reparation of fluorinated synthons.G reat achievements in the fields of fluorination and trifluoromethylation reactions have been realized over the past twenty years.[4] Theu se of reactive fluorinated building blocks,s uch as fluoroenol ethers or fluoroenolates,i s nevertheless an icea lternative.[5] Indeed, this approach allows an access to fluoro-or difluoromethylene-containing molecules without the limitations of direct fluorination reactions.M oreover, the second functional group which is generally introduced throughs uch reactions might serve for further synthetic elaboration. Aldol reactions with difluoroenolates are highly representative of this strategys ince ad ifluoromethylene group and ac arbonyl function can be introduced in as ingle step.T he preparation of a,a-difluoro-b-hydroxy ketones or esters through either Mukaiyama aldolo rR eformatsky-like reactions is well documented. [6,7] However, Mukaiyamareactions are often hampered by the poor stability of trimethylsilyl fluoroenol ethers,w hile Reformatsky reactions suffer from the drawbacks associated with the use of stoichiometrica mounts of organometallic reagents (basicand strictly anhydrousconditions,metallic wastes,… ). In this context, the trifluoroacetate relea...

The first transition-metal-free addition of alkyl nitriles to unactivated imines was developed using a catalytic combination of 4-MeOC(6)H(4)ONa and TMSCH(2)CO(2)Et to promote the reaction. The corresponding beta-amino nitriles are obtained in good to almost quantitative isolated yields under mild conditions. A mechanism involving an autocatalytic pathway is proposed on the basis of experimental observations.

The first domino aza-Michael/intramolecular-Michael reaction employing acrylamides as key ambivalent partners for the synthesis of δ-lactams is presented. It has been shown that the desired reactivity is contingent to the presence of an N- [a]