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The total synthesis of 8-epi, 8,9-epi, and 9-epi-(−)-cephalimysin A is described. Our catalytic enantioselective synthesis takes advantage of a novel tandem photoisomerization/Stetter reaction. The approach provides rapid access to the desired spirofuranone lactam core in good yield and excellent enantioselectivity. A late stage oxidation strategy allows for flexible access to three of the four diastereomers of cephalimysin A. Access to the epimers provides further support for the correction of the initially proposed relative stereochemistry of cephalimysin A.

N-Heterocyclic carbenes, prepared in situ from diarylimidazolium salts, serve as highly effective catalysts for the generation of reactive homoenolates from alpha,beta-unsaturated aldehydes. The catalyst-bound homoenolate reacts with electrophilic aldehydes leading, via the key intermediacy of an activated carboxylate, to gamma-butyrolactones in good yields and stereoselectivities. Importantly, this process demonstrates an unprecedented reaction mode for the generation of nucleophilic carbanions with a multifunctional organocatalyst under exceptionally mild and convenient reaction conditions.

A new electron-deficient chiral triazolium salt has been shown to catalyze the formation of quaternary stereocenters by an asymmetric intramolecular Stetter reaction. Pentafluorophenyl substitution on an aminoindanol-derived catalyst affords tertiary ether, thioether, and quaternary stereocenters in typically greater than 90% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction proceeds at room temperature under mild conditions to provide quaternary stereocenters with functional group relationships that are particularly difficult to access by other methods.

The changes in electron-density along the C–C bond-formation step in the N-heterocyclic carbene-catalyzed hydroacylation of unactivated double bonds has been studied by an electron localization function (ELF) analysis at the B3LYP/6-31G** level in order to characterize the reaction mechanism. Analysis of DFT reactivity indices and the natural bond orbital and ELF analysis at the most relevant points of the intrinsic reaction coordinate indicate that the reaction path takes place through a two-stage one-step mechanism with non-polar character. In the first stage a hydrogen atom is transferred from the hydroxyl group of Breslow intermediate 12 to the terminal olefinic carbon atom, to yield a pseudodiradical species. The barrierless C–C bond formation in this species constitutes the second stage of the reaction allowing the formation of the corresponding alcohoxy intermediate 13. The present theoretical study establishes that this mechanism is completely different to that involved in the intramolecular Stetter reaction, which is initialized by a polar Michael-type addition.

Enantioselective desymmetrization of cyclohexadienones via a d-camphor-derived triazolium salt catalyzed intramolecular Stetter reaction was realized. With 10 mol% of camphor-derived triazolium salt E and 10 mol% of DIEA, various substituted cyclohexadienones proceeded through an intramolecular Stetter reaction, affording tricyclic products in moderate to good yields and excellent ee.

An efficient method for the N-heterocyclic carbene (NHC)-catalyzed conjugate addition of acetyl anions to various α,β-unsaturated acceptors (Stetter reaction) has been optimized by using 2,3-butandione (biacetyl) as an alternative surrogate of acetaldehyde. The disclosed procedure proved to be compatible with microwave dielectric heating for reaction time reduction and with the use of different linear α-diketones as acyl anion donors (e.g. 3,4-hexanedione for propionyl anion additions). Moreover, the unprecedented umpolung reactivity of cyclic α-diketones in the atom economic nucleophilic acylation of chalcones is herein presented. Mechanistic aspects of the thiazolium-based catalysis involving linear and cyclic α-diketone substrates are also discussed.

A facile method for the intermolecular Stetter reaction of various Michael acceptors with acetaldehyde as a biomimetic acylanion source was realized using N-heterocyclic carbene catalysis. This catalytic system has also been applied to the enantioselective Stetter reaction and resulted in moderate to good enantioselectivities for the corresponding Stetter products.

A series of polyether-substituted thiazolium ionic liquids have been synthesized and used as catalysts in the Stetter reaction. The ionic liquids are a thermoregulated phase-separable catalysis (TPSC) system, because they possess the properties of critical solution temperature (CST) and inverse temperature-dependent solubility in toluene–heptane. The results showed that the novel TPSC system exhibits high recycling efficiency, and provides a potential route for a environmentally benign Stetter reaction.

The asymmetric intermolecular Stetter reaction is catalyzed by a novel triazolium salt derived N-heterocyclic carbene leading to 1,4-diketones in moderate to excellent yields (49-98%) and moderate to good enantioselectivities (56-78% ee), which could be enhanced by one recrystallization to excellent levels (90-99% ee).

The fluorous thiazolium salt 6 derived from 5-(2-hydroxyethyl)-4-methylthiazole was employed for an intramolecular Stetter reaction. The catalytic activity of the fluorous catalyst 6 was similar to that of the standard catalyst 1. The fluorous catalyst 6 survived multiple reaction cycles.

In the presence of cyanide ions as catalyst, aromatic and heterocyclic aldehydes can be smoothly added to α,β-unsaturated ketones, esters, and nitriles in aprotic solvents to form γ-diketones, 4-oxo carboxylic esters, and 4-oxo nitriles. Thiazolium salts in the presence of bases are also suitable catalysts; they permit not only addition of aromatic and heterocyclic aldehydes but also the addition of aliphatic aldehydes.

The cyanide catalyzed 1,4-Michael addition of aldehydes to α, β-unsaturated ketones has been examined with regard to substituent effects. Adjustment of the donor/acceptor relationship allows for the synthesis of multisubstituted diaryl 1,4-diketones.

The past decade of organic chemistry may be charcterized as a period of violent development of new synthetic methods. This was accompained by a systematization of the analysis of synthetic problems (synthetic strategy). The planning of the synthesis of an organic target molecule is greatly facilitated by distinguishing between reagents X(C)n … with normal reactivity (acceptor properties at C1,3,5…, donor properties at X, C2,4…) and with reactivity umpolung (acceptor properties at X, C2,4…, donor properties at C1,3,5…). In this context, reactivity umpolung turned out to be useful as a heuristic principle, as a classification scheme, and as an aid for locating so-called strategic bonds (synthon, transform, and antithesis according to E. J. Corey). There are six principal methods of umpolung: 1 2n-oxidation, heteroatom exchange and modification, homologation and its reversal, the cyclopropane “trick”, use of acetylenes, and redox reactions; under certain circumstances none of these techniques is necessary in cases where direct umpolung is possible. Throughout the article, normal reactivity is indicated by green print; reactivity umpolung by red print.

The first bio-inspired N-Heterocyclic Carbene (NHC)-catalyzed Stetter reaction in aqueous medium is reported with benzaldehyde and chalcone as model substrates. A screening of azolium salts as precatalysts revealed the remarkable efficiency of synthetic thiazolium salt 8 (up to 90% conversion in pure water at 75 °C). The reaction was successfully extended to various simple aldehyde substrates. The effect of temperature was also investigated in order to extend the reaction to lower temperature allowing a potential application to sensitive biomolecules. This study highlighted the influence of both solvent and temperature on the 1,4-diketone 3/benzoin 4 ratio. New precatalysts 26 and 27 were designed and synthesized to explore a possible compartmentalization of the reaction in aqueous conditions. Owing to the use of inexpensive metal-free N-Heterocyclic Carbene (NHC) as a bioinspired catalyst, we anticipate that this green strategy in aqueous conditions will be attractive for bioconjugation of many biomolecule-type aldehydes and enone derivatives.

This contribution aims at reporting on very recent advances achieved in controlled ring-opening polymerization of dilactones as promoted by easily accessible N-heterocyclic carbenes (NHCs). Even though carbenes have been known as very unstable species for long, more recently discovered NHC derivatives proved to display higher stability making their handling much easier and allowing their use as efficient catalysts in various organic reactions. Remarkably, these metal-free catalysts display high reactivity in synthesis of aliphatic polyesters such as polylactides and poly(β-butyrolactone)s all characterized by well-tailored compositions, molecular weight, tacticity, and end-group fidelity while presenting narrow to very narrow molecular weight distribution. Interestingly, novel macromolecular architectures based on such aliphatic polyester building blocks have been made available, e.g. multi-armed star shaped copolyesters, H-shaped copolyesters or macrocyclic polyesters paving the way to new biomedical applications for this family of important biocompatible and biodegradable aliphatic polyesters.

Thiazolium salt pre-catalysts have been immobilized on silica and monolithic polystyrene and their activity was tested under batch conditions in three model umpolung reactions, namely the benzoin condensation of benzaldehyde, the acyloin-type condensation of biacetyl, and the Stetter reaction of biacetyl with trans-chalcone. A prerequisite of the study has been the utilization of environmentally benign water and ethanol solvents. After having established the higher performance of polystyrene monolithic thiazolium carbene catalysts, their effectiveness has been tested under the flow regime by fabricating the corresponding monolithic microreactors (pressure-resistant stainless-steel columns). Importantly, it has been demonstrated by a brief substrate scope study that the polymeric matrix and the continuous flow regime synergistically contribute to preserve the activity of the carbene catalysts over time, thus permitting the long-term operation (up to 7 days) of the prepared monolithic reactors for the production of valuable compounds via the umpolung strategy.