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In the early eighties, we introduced samarium diiodide for the transformation of various functional groups. Since then, this reducing agent has been extensively used for the reductive cleavage of single bonds, C-C bond formations, C-N bond formations, and β-elimination reactions. In this Personal Account, we highlight our initial results, as well as some of the contributions from various research groups. Because of space limitations, we arbitrarily select some useful results that have recently been described in literature.

A series of chiral 10-heteroazatriquinanes were synthesized from enantiopure asymmetric cis-2,5-disubstituted pyrrolidines through a one-pot tandem cyclization procedure. The structures and configurations of these new chiral 10-heteroazatriquinanes are confirmed by X-ray single-crystal diffraction analysis.

The synthesis and detailed characterization of gold nanoparticles (AuNPs) inside human hair has been achieved by treatment of hair with HAuCl(4) in alkaline medium. The AuNPs, which show a strong red fluorescence under blue light, are generated inside the fiber and are arranged in the cortex in a remarkably regular pattern of whorls based on concentric circles, like a fingerprint. It opens an area of genuine nanocomposites with novel properties due to AuNPs inside the hair shaft.

The addition of Tf 2 O to some hydroxy steroids in the presence of excess base directly leads to steroidal olefins. This methodology is useful for the one-pot synthesis of Δ 2 - or Δ 3 -steroids under mild conditions from the corresponding alcohols.

A new analog 6a of diop is prepared from D-mannitol. The synthesis of the 1,3-diphosphine 9a and of 1,2-aminomonophosphine 12 are described. All these phosphines behave presumably as bidentate ligands, their efficiency in asymmetric catalysis are compared in a set of reactions involving asymmetric C-H or C-C bond formations.

A racemic mixture may be partially transformed in the presence of a chiral catalyst by kinetic resolution and formation of products with new structural features. If the starting material is fully consumed the products may still be enantiomerically enriched. The situation is summarized in the Introduction. A brief discussion on the regioselective transformations occurring on a racemic mixture under the influence of a chiral catalyst is presented in Section 2. Often stereo-differences occur, each enantiomer of the starting material resulting in a different product. It allows one to predict what the behaviour of some enantiopure substrates should be in presence of each of the enantiomers of a chiral catalyst. Many examples are presented in Section 3. The chiral substrates under consideration have two different reacting sites, usually of the same nature (OH, C=C, allylic positions, C—H for carbene insertion, epoxide fragment, etc.). In some cases the absolute configuration of the catalyst allows an excellent control of the regioselectivity. This approach is promising for the selective transformation of chiral molecules.

In the presence of chiral catalysts derived from the same chiral hexadentate ligand and aluminium, zinc or titanium ions, the reaction between cyclohexene oxide and trimethylsilyl cyanide can be controlled to give predominantly either the nitrile (up to 99% ee) or the isonitrile product (up to 94% ee). The metal ion, ligand stereochemistry and base concentration all play a role in determining the product ratio.

Chiral-2-substituted indolines are an important class of compounds with numerous applications in organic synthesis and as constituents of a number of biologically active molecules. Consequently, there has been a continued interest in the development of efficient methods for the syntheses of this class of chiral compounds. In this review, a detailed survey of the important efforts toward the synthesis of enantioenriched 2-substituted indolines by means of the kinetic resolution or the use of a chiral auxiliary in stoichiometric or catalytic processes is provided. The resolution of racemic mixtures through diastereomeric separation is not considered in the article.

The origin of nonlinear effects (no proportionality between enantiomeric excess (ee) of chiral auxiliary and ee of product) is first summarized in general terms, underlining the importance of the presence of molecular species bearing several moieties deriving from the chiral auxiliary. The presence of a heterochiral species, produced from enantioimpure chiral auxiliaries, usually explains well the deviation to linearity, especially asymmetric amplification. In this article it is shown that the absence of a heterochiral species is not incompatible with an asymmetric amplification. The demonstration has been done on a simple model, the equilibrium of homochiral dimerization. The monomers R and S being in equilibrium with the dimers R(2) and S(2), it was possible to calculate ee(monomer) and ee(dimer) as a function of the initial concentration and the initial ee of the monomer. The asymmetric amplification can be quite substantial for the dimer, while asymmetric depletion characterizes the residual monomers. Similar conclusions apply to homochiral tri- and tetramerizations. The extension to irreversible reactions was briefly analyzed as well as the use of these results.

The possibility of amplifying the small ee of a enantioimpure substance using a racemic reagent in kinetic resolution is discussed. A kinetic treatment of this problem along with some experimental proofs of the concept is presented. Simulation on kinetic resolution of small ee substrate by a racemic reagent showed an important enantioenrichment in the substrate ee, sometimes reaching close to absolute ee. Experiments of kinetic resolution of an amine of a small ee by a racemic acylating reagent gave a substantial amplification in ee of the amine. The possible transformation of an undetectable low ee in substrate to a detectable higher ee by using a suitable racemic reagent is also briefly discussed with help of calculations. The usefulness of asymmetric amplification by a racemic reagent is considered in the context of the biomolecular homochirality on earth.

We demonstrate the analytical potential of 2H-{1H} NMR spectroscopy in weakly ordering, chiral lyotropic liquid crystals made of poly(gamma-benzyl-L-glutamate) (PBLG) dissolved in chloroform or dichloromethane for investigating the intramolecular dynamic processes of four deuterated diaryls (derivatives of 1-(4'-methylphenyl)naphthalene). When the rotation of the aryl groups about the sp(2)--sp(2) bond is sufficiently slow relative to the NMR timescale, the method allows the spectral discrimination of enantiomeric atropisomers or enantiotopic directions in the prochiral derivatives. The effect of the position of substituents on the phenyl group on the conformational dynamics of these compounds has been examined as well as the nature of the organic co-solvent. When coalescence phenomena are observed, simulation of the experimental 2H-{1H} lineshapes using a formalism tailored for two deuterons undergoing mutual exchange allows the rate constants and the activation parameters for the internal rotation processes to be calculated. Experimental values of DeltaH(not equal) have been compared with data evaluated by molecular modelling calculations and the activation parameters are discussed for the various compounds. It is shown that these polypeptide mesophases have no significant impact on the interconversion dynamics of these compounds. In contrast with the nematic thermotropic phases, Haller's equation cannot be used to predict the evolution of the quadrupolar splittings (Deltanu(Q) values), and hence the order parameters, versus T in the PBLG mesophases. For these particular lyotropic systems, it is shown that an exponential function of the form Deltanu(Q)[Hz]=C x exp (-E/RT[K]) provides excellent agreement between the experimental and expected Deltanu(Q) values. Analysis of the results reported in this work suggests that orientation and chiral discrimination phenomena in these lyotropic solvents could be treated separately because they would involve different interaction mechanisms.

1,3-Dipolar cycloaddition of C-aryl-N-phenylnitrones to 3,5-bis-(arylidene)-1-methylpiperidin-4-ones affords novel mono- and bis-spiroisoxazolidines in moderate yields. In general, this reaction predominantly yields mono-spiroisoxazolidine, wherein the oxygen of the nitrone is linked to the β-carbon of the benzylidene moiety, while 3,5-bis-(2-chloro- and 3-nitro-benzylidene)-1-methylpiperidin-4-ones afford predominantly bis-spiroisoxazolidines. The cycloaddition of mono-spiroisoxazolidines occurs with facial diastereoselectivity to furnish bis-spiroisoxazolidines. The nitrogen in the heterocyclic ring of the 3,5-bis-(arylidene)-1-methylpiperidin-4-ones facilitates the cycloaddition through transannular (N⋯C O) and/or homoconjugative (N⋯C C) interactions.

The reaction of a racemic reagent on a mixture of enantiomers with small ee (ee = enantiomeric excess) has been studied for amine acylation. A substantial asymmetric amplification could be realized, for example, from 67 to > 95.5 ee. The combination of asymmetric amplifications is subsequently discussed. Two sequential asymmetric amplifications, one using a racemic reagent and another using a positive nonlinear effect allowed us to start from 1.5% ee and end with a large amount of a product of 97 % ee.

An historical account of the introduction of samarium diiodide in organic chemistry is presented in the first section, with the main initial results obtained. The basic organic transformations published in the author laboratory and by other groups during the initial period (1977–1987) are detailed. Some of the progresses subsequently obtained will be selected such as various transformations in synthesis, including asymmetric synthesis and total synthesis of natural products. The possible use of SmI 2 in catalytic amount together with a terminal reducing agent is discussed. In the conclusion is summarized the wide scope of the chemistry induced by SmI 2 with some comments on the future of this chemistry.

The principle of the one-pot multi-substrate screening is presented. This methodology has been successfully applied to various types of catalyzed enantioselective reactions: borane reduction of ketones, addition of organozinc on aldehydes, conjugate addition of diethylzinc on cycloalkenones or nitroal-kenes, hydroformylation of olefins, hetero-Diels-Al-der reaction on α-keto esters, enzymatic hydrolysis of glycerol-type monoesters as well as hydrogenation of 2-aryl-substituted terminal alkenes and enamides. The one-pot multi-catalyst screening methodology is also briefly discussed.

Promoted by catalytic amounts of Ni complexes tertiary α-hydroxyketones 1a , 3a – 5a undergo rearrangement, forming chiral isomers 1b , 3b – 5b . The best enantioselection was obtained with the model system 1-benzoylcyclopentanol 4a /2-hydroxy-2-phenylcyclohexanone 4b . In a ligand screening 2-[4-( S )- tert -butyloxazolin-2-yl]pyridine gave the highest enantiomeric excess of 46% ( S )- 4b . The analogous isomerisation reactions of α-hydroxyimines 6a , 7a forming chiral α-aminoketones 6b , 7b were established.

[4850-71-9] C7H8SO (MW 140.20) InChI = 1S/C7H8OS/c1-9(8)7-5-3-2-4-6-7/h2-6H,1H3/t9-/m1/s1 InChIKey = JXTGICXCHWMCPM-SECBINFHSA-N (chiral auxiliary) Physical Data: bp 90 °C (0.2 mm), [α]D+ 147 (acetone). Solubility: soluble in EtOAc and CH2Cl2. Form Supplied in: white solid. Handling, Storage, and Precautions: recommended storage at temperature range: 2–8 °C. Skin/eye contact and inhalation should be avoided.

The addition of Et2Zn on benzaldehyde in the presence of a stoichiometric amount of Ti(Oi-Pr)4 catalysed by (1R,2R)-bis(trifluoromethanesulfonamido)-cyclohexane 1a has been revisited. A nonlinear effect was present or absent, depending on the catalyst preparation. An asymmetric amplification has been observed when Ti(Oi-Pr)4 was added to 1a followed by Et2Zn and then benzaldehyde (Ohno procedure). In the alternate procedure (Walsh), where Et2Zn and 1a were premixed, there is linearity. Mechanistic implications are discussed.

The kinetic resolution of 4-acetyl[2.2]paracyclophane has been realized by borane reduction in the presence of a CBS catalyst. The structure of the two diastereomeric alcohol products has been established. The ketone was recovered in more than 99% e.e. at 69% conversion.

The fundamental principles of non-linear effects (NLE) are reviewed. Particular emphasis is placed on the case of asymmetric amplification, since it allows one to perform useful chemistry with a non-enantiopure chiral auxiliary. A strong asymmetric depletion in a catalytic reaction may lead to an underestimation of the actual enantioselectivity of the fully resolved ligand. The study of NLE's is also proving useful as a mechanistic tool in asymmetric catalysis. Similar concepts may be extended to chiral reagents or to kinetic resolution. 1. What is a Non-Linear Effect in Asymmetric Synthesis? 2. The Conditions for Observing a Non-Linear Effect in Enantioselective Catalysis 3. Some Simple Models of NLE in Enantioselective Catalysis 4. Comparison of the Sizes of Asymmetric Amplifications 5. Rates and Non-Linear Effects in Asymmetric Catalysis 6. Non-Linear Effects Involving Chiral Reagents 7. Mechanistic Applications of Non-Linear Effects 8. Synthetic Applications 9. Concluding Remarks

A chiral catalyst or reagent may be used to create an asymmetric center on the components of a racemic mixture. The quantitative relationships between the various experimental data (ee's, fractional amounts of products, conversion) are given, and extended to the formation of regioisomeric products. The cases when products are not isomeric are also considered. The meaning of ‘kinetic resolution’ in these processes is discussed. Finally, it is shown that above results can be used to safely predict the behavior of a chiral substrate versus either enantiomers of a chiral catalyst or reagent. Indeed, regio-, diastereo- or chemoselective reactions on a chiral substrate can be achieved by the choice of the absolute configuration of an external chiral controller.

The advantages and disadvantages of using enantiomeric excess, enantiomeric composition or enantiomer ratio to describe a mixture of enantiomers, are discussed with respect to various stereochemical situations.

Trimethylsilylcyanide has been added to a number of aldehydes using a highly active chiral catalyst. This procedure gives the TMS ethers of the corresponding cyanohydrins in excellent chemical yields with enantiomeric excesses of up to 59%. The reaction is believed to occur through hypervalent silicon intermediates.

Studies have been carried out on the addition of trimethylsilylcyanide to aldehydes using highly active chiral lithium phenolate catalysts. The screening of a number of chiral phenolates has resulted in a system which gives the TMS ethers of cyanohydrins in excellent chemical yields with enantiomeric excesses of up to 97%.

Chiral 1,2-bis(phosphanes) 13, devoid of individual chiral centers, have been prepared in three steps from chiral sulfoxide 10. Their corresponding rhodium complexes were used as catalysts for asymmetric hydrogenation, giving high ee values (⩽ 95%) in the reduction of itaconic acid or its ester. A cationic rhodium complex involving coordination of two molecules of 13b and one molecule of oxygen has been isolated and its crystal structure established.

Several enantiopure diphosphanes 21 were synthesized in three steps from a common precursor 19. The cationic rhodium complexes 22 were screened as catalysts for asymmetric hydrogenation of various alkenes. Enantioselectivities up to 95−98% have been observed in some cases. Enantioselectivities are modest in allylic substitution catalyzed by the corresponding palladium complexes.

For more than a century, organic chemists have been playing in Nature's laboratory. Their first goal was to understand the organization of atoms in the living matter and then to reproduce it by synthesis. This quest gave rise to several efficient techniques to synthesise molecules; many of them still in use nowadays, as such or with little modifications. Even at the beginning of this journey, the chemists discovered that their methods were far from being as efficient as the ones used by Nature to produce substances. The natural molecules were chiral and there was even an enantiomer that was produced over the other;a lesson of perfection. This was another challenge for the chemists and they succeeded by first developing techniques to separate enantiomers and more recently reagents and reactions to produce only the desired stereoisomer. Asymmetric synthesis uses chiral auxiliaries, reagents or catalysts to create chirality into the desired compound. The common perception, as a minimum condition, was that the chiral substance used to perform such a transformation has to be of the highest enantiomeric purity to obtain a very high selectivity. The relation between the enantiomeric excesses of the chiral substance and the product was suggested to be linear. But there were a lot of surprises left in the laboratory. Who would have thought that an impure substance could give an enantiomeric excess in the product higher than its own purity? The molecules are acting in different ways in solution. Self-organization and aggregation can arise depending on the structure of the substance or its environment. Such phenomenon can generate deviations to the awaited behaviour of the molecules that can be observed in many cases. This article tries to present some examples of the historical reports of such peculiar behaviours, their influence on physico-chemical properties and the final discovery of the now well-known nonlinear effects in asymmetric synthesis.Key words: asymmetric synthesis, diastereomeric interactions, nonlinear effects.

Diferrocenylphosphine-borane has been synthesized in three steps from monolithio- ferrocene. This compound may be transformed into the corresponding phosphide which is a nucleophilic reagent allowing to introduce the diferrocenylphosphino grouping in organic compounds. Several chiral diphosphines related to DIOP have been synthesized by this method. The corresponding rhodium complexes are catalysts in the hydrogenation of various C=C double bonds.

Tenatoprazole, a substituted imidazopyridinyl derivative, is an irreversible proton pump inhibitor (PPI), which is used for the prevention and treatment of gastric acid-related diseases. A new highly efficient asymmetric oxidation using cumene hydroperoxide (CHP) as the oxidant in the presence of titanium tetraisopropoxide (Ti(O i Pr) 4 ) and (+)-(1 R ,2 S )- cis -1-amino-2-indanol, in a polar aprotic solvent at 0–20 °C, has been developed to prepare tenatoprazole with an enantiomeric excess of >99%, a chemoselectivity of >90% and a chemical yield of >90% from the corresponding sulfide. This procedure was successfully implemented on scales ranging from 100 mg to multiple kilograms. Detailed studies of the parameters controlling purity and yield for this reaction are presented.

Kinetic resolutions with enantioimpure chiral auxiliaries (reagents or catalysts) are considered, and a kinetic treatment for various rate laws is described. A useful parameter, the apparent stereoselectivity factor, is defined and correlated to the enantiomeric excess of the chiral auxiliary. Deviations from the regular laws are possible (asymmetric amplification or depletion). These anomalies have their origins in the same phenomena that cause nonlinear effects in enantioselective catalysis. Asymmetric amplifications have been experimentally observed.

Enantiopure 2-hydroxy-2′-amino-1,1′-binaphthyl (NOBIN) is shown to catalyse C-alkylation of aldimine Schiff's bases of alanine ester under phase-transfer catalysis conditions (solid NaOH or NaH, toluene, ambient temperature, 10% NOBIN). Using (R)-NOBIN, the final (S)-α-methylphenylalanine was obtained in up to 68% ee.

Several chiral 1,2- and 1,3-hydroxythiols derived from ( R )-camphor, (1 S )-(+)-10-camphorsulfonyl chloride, cysteine and cystine derivatives were prepared and evaluated as catalysts in borane ketone reductions. Under the best experimental conditions (10 mol% catalyst, THF, 35°C), a 95% yield of ( R )-1-phenylethanol of 64% ee was obtained in the borane reduction of acetophenone.

Diiodosamarium prepared in tetrahydropyran reduces allylic, benzylic and alkyl halides at 0 or −15°C to give organosamariums which are stable under these conditions. The reactivity of these organometallics has been explored, showing that they are very selective reagents.

Fast optimization of a chiral catalyst and chiral ligands prepared by combinatorial chemistry are reviewed. The case of a one-pot multi-substrate screening of a chiral catalyst has been also discussed.

Treatment of cerium dioxide with small amounts of RuCl3. 3H2O allows the mild preparation of an efficient heterogeneous system for the dioxygen oxidation of various alcohols and aldehydes.

Nonlinear effects (NLEs) have been used as a new tool to characterize the various modifications of a chiral titanium complex used in stoichiometric or catalytic mode in asymmetric sulfoxidation by cumyl hydroperoxide. Spectacular changes from (+)- to (−)-NLEs were observed for minor modifications of the experimental conditions.

Compound (4R,5R)- or (4S,5S)-2,2-dimethyl-α,α,α′,α′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (TADDOL) was shown to catalyze C-alkylation of aldimine Schiff's bases of alanine esters under phase-transfer catalysis conditions (solid NaOH, toluene, ambient temperature, 10% TADDOL) with the e.e. of the final α-methylphenylalanine or α-allylalanine reaching 82%.

A nonlinear effect (NLE) between the ee s of diisopinocampheyl chloroborane ( ee aux ) and the ee s of 1-phenylethanol ( ee prod ) has previously been observed during the reduction of acetophenone. The size of this asymmetric amplification is related to the amount of Ipc 2 BCl used to perform the reduction, as we report in this communication.

Acid chlorides react with esters in the presence of samarium diiodide and catalytic amounts of NiI 2 to afford samarium enediolates which can further react with electrophiles such as water or aldehydes to give respectively α-ketols or α-dihydroxyketones.

The catalytic asymmetric reduction of different ketones1 with transient hypervalent silicon hydrides is described. Trialkoxysilanes, upon activation by a small amount of a chiral nucleophile, underwent addition to the carbonyl group, forming the corresponding silyl protected alcohols, which were cleaved during the workup to give the enantiomerically enriched product alcohols. A brief screening of the reaction parameters and the results are summarized below.

Diiodosamarium prepared in THP reduces allylic iodides and bromides at 0 or −15 °C to give organosamarium compounds which are stable under these conditions. These allylic samarium compounds react with many functionalities including the keto group of keto esters. Benzylic samarium compounds were prepared similarly from benzylic bromides.