Professor Henri Boris Kagan

Denis Chusov

Gary A Molander

Virginie Ratovelomanana-Vidal

Olivier Riant

Emmanuelle Schulz

# A N Nesmeyanov

A Pioneering Career in Catalysis

Keywords: asymmetric hydrogenation, asymmetric oxidation, nonlinear effects in asymmetric catalysis, origin of chirality, samarium iodide

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Early contributions

The passion of Henri Kagan toward chirality makes him a true heir of Louis Pasteur, one of the fathers of stereochemistry who first isolated the enantiomers of tartaric acid in the early 19th century. To understand this attraction for chirality more thoroughly, the influence of his early mentors, Jean Jacques and Alain Horeau, were pivotal toward this field. Henri Kagan was first hired by Jean Jacques at the Collège de France to work in the field of steroids (Figure 1). During his PhD, he first came up with the idea of preparing the so-called inversed steroids (Figure 2). The different biological activities of enantiomers were well known at that time, and the idea of Henri Kagan was that inversed steroids might present antihormone activities. Thus, during his PhD, which he presented in March 1960, he devised several syntheses to prepare such compounds. For instance, the first example was a model of an inversed cortisone, prepared in about 12 steps from dehydroepiandrosterone [START_REF] Kagan | Un nouveau type de stéroïdes modifiés ; les stéroïdes « inversés ». Synthèse d'une cortisone « inversée » (Inverted steroids. IV. First approximation of an "inverted" cortisone)[END_REF] . Despite the lack of biological activities, this first entry in the field of chirality was the foundation of his love for stereochemistry. This was further consolidated by his interactions with Alain Horeau (one of the pioneers in the field of resolution and in the determination of absolute configurations by chemical methods), who hired Henri Kagan in 1962 as a vicedirector of the Laboratoire de Chimie Organique des Hormones, with the offer to start his own research projects. His work with Alain Horeau on organometallic reagents (e.g., Reformatsky reagents) and partial resolution led Henri Kagan to start to develop novel ideas for the construction of stereocenters using chiral reagents and/or chiral substrates. Some representative examples of his early achievements are presented in Figure 3: A first attempt was reported in 1968, with one of his PhD students, as they attempted to reduce acetophenone with chiral amines/borane adducts 2 . Although the optical yields were at this time very modest, this could be regarded as an early attempt of reagent activation by a chiral base. The diastereoselective reduction of glyoxylate esters was also studied with a lithium aluminum hydride reagent modified by cinchonine, with a modest optical yield of 5% 3 . However, the positive effect of combining a chiral menthyl ester and the chirally modified reducing agent led to an improvement to 26%, while the unmodified hydride reagent gave only a 10% optical yield on the chiral ester, and this was later recognized as the Match-Mismatch effect in asymmetric synthesis. This idea was later applied to the preparation of enantiomerically enriched amino acids, using either substrates bearing two chiral fragments (addition of Grignard reagents on activated imines 4 ) or the combination of two chiral substrates (carbene insertion onto an N-H bond [START_REF] Nicoud | Une nouvelle synthèse asymétrique de l'alanine par insertion d'un carbène sur une liaison N-H (New asymmetric synthesis of alanine by carbene insertion into a nitrogen-hydrogen bond)[END_REF] ). In each case, the influence of the Match-Mismatch effect was confirmed.

Figure 3. Novel ideas for the construction of stereocenters using chiral reagents and/or chiral substrates

Henri Kagan is now widely recognized as being the pioneer in many fields related to asymmetric catalysis and lanthanide chemistry, but some earlier works, dealing with various aspects of photochemistry, could also be considered as equally important, although less recognized.

Figure 4. Stereoinduction by circularly polarized light

Indeed, in the early 1970s, as was the case for many scientists, Henri Kagan was searching for new theories on the appearance of chirality on earth (homochirality), and his work on the determination of absolute configurations of non-racemic molecules led him to investigate the influence of Circularly Polarized Light (CPL) on the course of a stereoselective reaction. The formation of helicenes was chosen as a model, and Kagan and coworkers studied the photocyclization of stilbenes into [6]helicene by CPL (Figure 4). The measurement of the optical rotation of the products was in full agreement with an asymmetric induction by the right-or left-CPL, with enantioselectivities around 0.21%. Even if this enantioselectivity appears very modest (it was shown later that enantioselectivities are ultimately limited by the Kuhn anisotropic factors g), this result, along with the work of Calvin 6 , paved the way for a fascinating area of research which is still very active now to explain the phenomenon of chirality on earth 7 . In a later publication, Kagan and coworkers investigated a complementary pathway for generating chirality by CPL photodegradation of racemic compounds. Although such reactions required almost full conversions (> 99%), of the starting material, significant enantiomeric excesses (up to 36%) were obtained for the photodecomposition of racemic camphor into -campholenic aldehyde, via a Norrish Type I cleavage mechanism [START_REF] Balavoine | Preparation of chiral compounds with high optical purity by irradiation with circularly polarized light, a model reaction for the prebiotic generation of optical activity[END_REF] .

The group continued some research in the field of photochemistry and published in 1973 one of the very first examples of an enantioselective reaction enabled by Triplet Energy Transfer via a chiral photosensitizer. Indeed, the photoderacemization of a racemic sulfoxide by a chiral naphthylamide led to a photoequilibrium of around 4% ee [START_REF] Balavoine | Photoactivation optique du methyl p-tolyl sulfoxide racémique par emploi d'un photosensibilisateur chiral (Optical photoactivation of racemic methyl p-tolyl sulfoxide using a chiral sensitizer)[END_REF] . Similarly, Kagan et al. investigated photochemical transformations, such as the photoequilibration of sulfoxides, in chlolesteric crystal media, albeit with low to negligible ees [START_REF] Eskenazi | Asymmetric induction in cholesteric media revisited[END_REF] . Finally, it should be noted that his visionary thinking led, in 1978 (around the same time as that of leading scientists such as J.-M. Lehn and J. P. Sauvage), to the description of one of the first examples of hydrogen photoproduction, using Ru(bipy) 3 2+ as a photocatalyst 11 .

Because of his longstanding interest in the field of asymmetric hydrogenation, Henri Kagan was also regularly involved in the design of chiral ligands for such applications. This was the opportunity to become involved in the field of the conception of ferrocenyl derivatives with planar chirality, and he designed two efficient methods based on ortho lithiation strategies.

The first method (a), starts from a chiral actetal, easily prepared from ferrocene carboxaldehyde and a chiral triol auxiliary 12 . Diasteroselective ortho lithiation was carried out with tert-butyllithium in diethyl ether at -78 °C, followed by electrophilic capture of the lithio-intermediate. After removal of the chiral auxiliary by hydrolysis of the acetals, the planar chiral ferrocenyl aldehydes were obtained in high yields and 98% ees. A second method was even more efficient to introduce two different groups on two ortho positions of a ferrocene structure, starting with either enantiomer of ferrocenyl-p-tolyl sulfoxide, easily prepared in one step from ferrocene though the Andersen method. The ortho lithiation was here carried out with LDA in THF and delivered, after electrophilic capture, the ortho-substituted aldehydes with high des (98%) [START_REF] Rebière | Asymmetric synthesis and highly diasteroselective ortholithiation of ferrocenyl sulfoxides. Application to the synthesis of ferrocenyl derivatives with planar chirality[END_REF] . The sulfoxide was then easily replaced by sulfur-lithium exchange with tert-butyllithium and electrophilic capture of the lithio intermediates 14 . Those methods were widely used by Kagan and other groups for the preparation of chiral metallocene derivatives with planar chirality, including chiral ligands 15 .

Figure 5. Ferrocenyl derivatives with planar chirality

Early in his carrier, Henri Kagan investigated the use of reagents and catalysts supported or inserted into solid supports, as potentially convenient systems for reagent handling and recovery, but as well to evaluate the influence of the support on the reaction outcome. Graphite was the support of choice in such studies, which included graphite bisulfate as a catalyst for Fischer esterification and aromatic nitration, antimony pentachloride-graphite for halogenation reactions, and xenon hexafluoridegraphite for fluorination reactions [START_REF] Bertin | Graphite electrolytic lamellar reagents in organic chemistry. Esterifications in the presence of graphite bisulfate[END_REF] . After the discovery of 2,3-O-isopropylidene-2,3-dihydroxy-1,4bis(diphenylphosphino)butane (DIOP), Kagan, Setton and coworkers immobilized a DIOP analog on oxidized graphite and studied the performance of the corresponding rhodium catalyst in enantioselective dehydroamino acid-hydrogenation 17 .

Contributions to Asymmetric Hydrogenation and Hydrosilylation

The homogeneous asymmetric hydrogenation of prochiral unsaturated compounds catalyzed by transition metal complexes is undoubtedly one of the most efficient and straightforward methods to access enantiomerically en-riched molecules. The seminal work of Professor Kagan played a crucial role with outstanding discoveries in this arena that contributed to the explosive flurry of activities and paved the way for global research and implementation of asymmetric hydrogenation methods. The pioneering developments of Knowles [START_REF] Knowles | Catalytic Asymmetric Hydrogenation employing a Soluble Optically Active, Rhodium Complex[END_REF] and Horner [START_REF] Horner | Asymmetric Catalytic Hydrogenation with an Optically Active Phosphinerhodium Complex in Homogeneous Solution[END_REF] in 1968 demonstrated that a chiral version of soluble Wilkinson - type rhodium complexes [START_REF] Osborn | The preparation and Properties of Tris(triphenylphosphine)halogenorhodium(I) and Some Reactions thereof including Catalytic Homogeneous Hydrogenation of Olefins and Acetylenes and Their Derivatives[END_REF] containing optically active tertiary phosphine ligands enabled enantioselective hydrogenations of unsaturated olefins, albeit with low enantioselectivities (< 15% ee). In 1971, Morrison and coworkers reported the hydrogenation of atropic acids and (E)-α-methylcinnamic acid using a Rh(I)diphenylneomenthylphosphine (NMDPP) catalyst system with up to 61% ee. [START_REF] Morrison | Asymmetric Homogeneous Hydrogenation with Rhodium(I) Complexes of Chiral Phosphines[END_REF] Only a few reports related to asymmetric hydrogenation using soluble rhodium complexes were reported when H. B. Kagan started to work in this area in 1971, looking for a rational approach to prepare a chiral catalyst and to demonstrate the usefulness of a chiral diphosphine Rh(I) complex. Professor Kagan postulated that the ligand conformation should possess maximum rigidity, and that the ligands must stay bound to the metal to avoid epimerization equilibria to reach a high level of stereoselectivity. Phosphines such as R*-P(C 6 H 5 ) 2 , where R* is chiral, were chosen to increase the steric control introduced by the R* group with the idea of decreasing the flexibility around the R*-P bond. In this context, ligands with a twofold axis of symmetry were prepared from inexpensive, readily available tartaric acid enantiomers after protection of the diol derivatives. This major contribution anticipated the success of bidentate diphosphines, which involved chelation of the ligand as a prerequisite to achieve high level of enantioselectivities.

Because

((2R,3R)-2,3-dimethoxybutane-1,4diyl)bis(diphenylphosphine) was not an efficient asymmetric catalyst, the idea was to reduce the flexibility of the seven-membered chelate ring with the rhodium by introducing a dioxolane ring. From this was created (-)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphinobutane [(-)-DIOP], which was prepared as a crystalline diphosphine from (+)-tartaric acid. [START_REF] Dang | The Asymmetric Synthesis of Hydratropic Acid and Amino-Acids by Homogeneous Catalytic Hydrogenation[END_REF] (-)-DIOP was easy to synthesize, purify and store, and thus represented the first chiral bidentate phosphine ligand -a major breakthrough in asymmetric catalysis that demonstrated Kagan's exceptional creativity in the field of stereochemistry (Figure 6). (-)-DIOP provided among the best results in asymmetric hydrogenation achieved at this time (Figure 7). The Rh(I) chiral complex was synthesized in situ starting from [RhCl(Olefin 2 ) 2 ] obtained from RhCl 3 by adding the chiral phosphine ligands to provide a displacement of olefins. The Rh-DIOP-catalyzed asymmetric hydrogenation of olefins was usually performed under extremely mild conditions using a catalyst ratio of S/C=100. Pioneering experiments were carried out on atropic acid and their derivatives (Figure 8), albeit with moderate enantioselectivities up to 25% ee. Careful experiments demonstrated the beneficial role of Et 3 N in these transformations, with the best asymmetric induction achieved with the hydrogenation of atropic acid, providing the reversed (S)-configuration of the reduced product (with up to 63% ee). Several α-Nacylamino-α-acrylic acids and their derivatives were hydrogenated using the Rh-(-)-DIOP catalytic system delivering the corresponding α-amino acids (Figure 9). The S/C ratio showed no influence on the stereochemical course of the hydrogenation. Alternatively, the natural (S)-amino acids were accessible by using (+)-DIOP enantiomer. This paper provided an extensive study of the hydrogenation of various precursors of alanine, phenylalanine, tyrosine, Dopa, and leucine using the Rh-(-)-DIOP catalyst system and detailed the parameters that influenced both the enantioselectivities and the rate of the hydrogenation. [START_REF] Kagan | Asymmetric Catalytic reduction with Transition Metal Complexes. I. A Catalytic System of Rhodium (I) with (-)-2,3-O-Isopropylidene-2,3dihydroxy-1,4-bis(diphenyl-phosphinobutane, a New Chiral Diphosphine[END_REF] As a demonstration of its significance, the publication highlighting these achievements has been cited over 1,100 times and viewed over 4,100 times.

Figure 9. Asymmetric hydrogenation of -Nacylaminoacrylic acid derivatives

Surprisingly, substituents on the phenyl ring of the acetamidocinnamic acid derivatives seemed to increase the enantioinductions in the hydrogenation reactions. The meticulous work of Professor Kagan showed an effective enantioinduction of 83% (not shown) vs 73% (Figure 9) for the reduction of an N-acetyl phenylalanine precursor measured by v.p.c. analysis with a clean separation of the two enantiomers of the N-acetyl phenylalanine. [START_REF] Kagan | Asymmetric Catalysis by Chiral Rhodium Complexes in Hydrogenation and Hydrosilylation Reactions[END_REF] Kagan also studied the catalytic activity of Wilkinson's rhodium complexes with various diphosphines in the hydrogenation of -acetamidocinnamic acid and styrene, demonstrating the influence of the chain linking the diphenylphosphino groups in changing the selectivity of the catalyst. [START_REF] Poulin | Hydrogénation Catalytique Homogène à l'aide de complexes Rhodium-Diphosphines[END_REF] Professor Kagan anticipated very early the crucial role of steric parameters in the Rh-catalyzed homogeneous hydrogenation of olefins. The group followed up this chemistry by designing novel ligands with the idea to evaluate the influence of steric parameters on the reduction (Figure 10). Various modified DIOP ligands L1-L3 bearing methyl substitutions at different positions on the phenyl ring were developed as well as L4-L5 with modifications on the dioxolane part to evaluate their catalytic properties compared to the parent (-)-DIOP ligand. [START_REF] Dang | Réduction Asymétrique Catalysée par des Complexes de Métaux de Transition III. Diphosphines Chirales Derivées de l'Isopropylidène Dihydroxy-2,3 Bis(DiphenylPhosphino)-1,4 Butane (DIOP)[END_REF] Notably, the influence of methyl substitutions on the phenyl ring of the DIOP was investigated for the Rh-catalyzed hydrogenation of N-acetyl phenylalanine precursor, demonstrating that substitution of a methyl group at the meta position of the aryl ring of the (-)-DIOP such as in L3 increased both the enantiomeric excess and the rate of the hydrogenation reaction (up to 88% ee vs 82% ee), although L1 bearing a methyl group at the ortho position of the phenyl ring as well as 2,5-disubstituted methyl groups in L2 led to lower enantioinductions compared to the (-)-DIOP parent ligand. Enantioselective synthesis of phenylalanine derivatives has been accomplished with [Rh-(+)-DIOPCl], demonstrating that the enantioselectivity was influenced by the stereochemistry of the double bond, the para-substituent on the N-benzoyl group, and the esterification of the carboxylic acid group. 27

Figure 10. Chiral diphosphines related to (+) and (-)-DIOP

Notably, the synthesis of the precursor of DOPA, a useful drug against Parkinson's disease, was also improved to 90% ee (vs 86% ee) using L3 (Figure 11), although asymmetric hydrogenation performed with L6 as a chiral ligand having the phenyl ring ortho-linked to form a phosphole system afforded low ee, interestingly with a reversed (S)-configuration.

Figure 11. Asymmetric synthesis of DOPA intermediates

Together with J. C. Fiaud at Paris-Sud University, H. B. Kagan designed a novel ligand derived from DIOP L7 bearing two methyl groups on the alkyl side chain next to the phosphorus atom. [START_REF] Kagan | Synthesis of New Chiral Phosphines for Asymmetric Catalysis[END_REF] Similar results were obtained with the asymmetric synthesis of N-acetyl alanine with good enantioselectivity, although N-acetyl phenylalanine was produced with the opposite configuration in comparison to DIOP itself. They postulated that the conformation of the seven-membered ring chelate involving the rhodium and phosphorus atoms must be modified by introduction of two methyl substituents. Later, Cyclodiop L8 [START_REF] Zhang | Cyclodiop, an example of a new class of chiral diphosphines[END_REF] with a P-P bond was prepared and catalyzed the reduction of (Z)-Ph=C(NHAc)COOH into (R)-Nacetylphenylalanine with 71% ee.

In a somewhat related contribution and to confirm the influence of the oxygen atom, a cyclopentane analogue of (-)-DIOP L9 prepared from trans-cyclopentane-1,2dicarboxylic acid was used in the reduction of acetamido cinnamic acid derivatives exhibiting lower enantiofacial discrimination to deliver the corresponding (R)-N-acetyl phenylalanine (63% ee vs 82% ee), although a comparable level of enantioinduction was attained with ligand L10 (Figure 12). These results clearly showed that steric factors played a key role in the asymmetric hydrogenation.

In addition to the development of related DIOP diphosphines, Professor Kagan contributed to the development of various novel chiral diphosphines, demonstrating his continuing research interests in stereochemistry and asymmetric catalysis. As such, PHELLANPHOS L11 [START_REF] Lauer | Synthesis of phellanphos, an efficient chiral 1,2-diphosphine for asymmetric catalysis[END_REF] and NOPAPHOS L12, which chelated with the rhodium with a rigid conformation, were prepared and their structures were confirmed by X-ray analysis. [START_REF] Samuel | New Diphosphines for Asymmetric Catalysis[END_REF][START_REF] Samuel | Sterochemistry and Structure of Phellanphos and Nonaphos, two Chiral Diphosphines for Asymmetric Hydrogenation[END_REF] (S,S)-L11 and(R,R)-L12 gave δ and λ chelated rings. The cationic [Rh(COD)-PHELLANPHOS] + PF 6 -(COD=1,5cyclooctadiene) complex exhibited excellent catalytic properties in asymmetric hydrogenation to access (R)-Nacetyl phenylalanine and (R)-N-acetyl alanine in quantitative yields and 95% enantioselectivities. Later, together with J. Ward and A. Börner at Paris-Sud University and Rostock University, H. B. Kagan explored the catalytic performances of alkyldiphenylphosphine-rhodium complexes having as an additional ligating functional group a hydroxyl substituent in a rigid (hydroxy NORPHOS, L13) [START_REF] Ward | Synthesis of 6-endo-Hydroxy Norphos, a Potential Ligand for Construction of Chiral Bimetallic Catalysts[END_REF] or a flexible framework [(S)-1,2 bis(diphenylphosphino)butane-4-ol L14] from L-ascorbic acid. [START_REF] Börner | Synthesis and Catalytic Properties of an Acyclic Analogue of Hydroxy Norphos[END_REF] Lower enantioselectivities and reaction rates were observed with the cationic complex prepared from acyclic analogue L14 during the hydrogenation of N-acetyl dehydrophenylalanine and its methyl ester compared to the rigid catalyst derived from hydroxy NORPHOS L13. H. B. Kagan and A. Börner hypothesized that a prochiral substrate having a C=C double bond should be able to interact with the ligand both at the catalytic center and with the pendant Lewis acid. During the course of the group investigations, they also prepared the first chiral bimetallic complex based on a boron analogue of DIOP L15. [START_REF] Börner | A Boron Analog of DIOP: Synthesis and Properties[END_REF] The corresponding neutral [RhClL15] and cationic [Rh(COD)L15] + BF 4 -catalysts were less stereoselective than (-)-DIOP for the reduction of N-acetyl dehydrophenylalanine, but comparable enantioselectivities were achieved for the reduction of ketopantolactone (Figure 12).

Figure 12. Other diphosphine ligands

Enamides [START_REF] Suen | Propriétés d'acylimines et acylénamines[END_REF][START_REF] Gopalaiah | Use of Nonfunctionalized Enamides and Enecarbamates in Asymmetric Synthesis[END_REF] are exceptional prochiral substrates to access enantiomerically enriched amides and amines, which are biorelevant targets and valuable building blocks of synthetic interest. After the discovery in 1971 of the seminal Rh(I)-DIOP-catalyzed asymmetric hydrogenation of N-acyl dehydroamino acid and of a non-functionalized enamide, [START_REF] Kagan | Asymmetric Catalytic reduction with Transition Metal Complexes. I. A Catalytic System of Rhodium (I) with (-)-2,3-O-Isopropylidene-2,3dihydroxy-1,4-bis(diphenyl-phosphinobutane, a New Chiral Diphosphine[END_REF] Kagan's group investigated the hydrogenation of a range of enamides with up to 85% enantioselectivities and (R) or (S) inverted configurations, demonstrating the crucial role of solvents used for the transformation (Figure 13). [START_REF] Kagan | Réduction Asymétrique Catalysée par des Complexes de Métaux de Transition IV. Synthèse d'Amines Chirales au moyen d'un Complexe de Rhodium et d'Isopropylidene dihydroxy-2,3 bis(diphenylphosphino)1,4 butane (DIOP)[END_REF]

Figure 13. Asymmetric hydrogenation of enamides using Rh-(+)-DIOP

A stable cationic [Rh(COD)(+)DIOP] + ClO 4 -complex successfully achieved the asymmetric hydrogenation of Nacetyl-1-phenyl-1-aminopropene with up to 92% ee. [START_REF] Sinou | Catalyse Asymétrique par le Complexe Cationique [Rh(COD)(+)-DIOP] + ClO 4[END_REF] Stereoselective syntheses of dipeptides [START_REF] Poulin | Synthèse Asymétrique de Dipeptides par Réduction d'un Bisdéhydrodipeptide[END_REF][START_REF] Poulin | Stereoselective Synthesis of Dipeptides by Asymmetric Reduction of Dehydropeptides Catalyzed by Chiral Rhodium Complexes[END_REF][START_REF] Poulin | A Direct Preparation of Acetyl-(S)-phenylalanyl-(S)-Phenylalanine Methyl Ester by a Double Asymmetric Hydrogenation[END_REF][START_REF] El-Baba | Asymmetric Homogeneous Reduction of Dehydropeptides[END_REF][START_REF] El-Baba | Tandem Asymmetric Syntheses from Achiral Precursors. Asymmetric Homogeneous Reduction of Bisdehydrodipeptides[END_REF] were also efficiently obtained using neutral [RhCl(-)-DIOP] and cationic [Rh(COD)(+)-DIOP] + BF 4 -catalysts, as well as the Rh/DIPAMP complex. H. B. Kagan was not only interested in transition metal catalysis involving rhodium complexes, but he also designed and characterized the structure of a novel [IrCOD(+)-DIOPCl] catalyst, which was confirmed by Xray analysis. [START_REF] Brunie | Catalyse Asymétrique et Structure du Complexe IrCOD((+)diop)Cl[END_REF] Because very little attention had been paid to the utilization of optically active hydrocarbon ligands, H. B. Kagan used titanium (IV) complexes containing menthyl (M)-and neomenthyl (NM) η 5 -cyclopentadienyl ligands, (η 5 -MCp) 2 TiCl 2 and (η 5 -NMCp)(η 5 -Cp)TiCl 2 to hydrogenate simple olefins such as 2-phenyl-1-butene. [START_REF] Cesarotti | Complexes with Chiral Alkylcyclopentadienyl Ligands for Homogeneous Catalytic Asymmetric Hydrogenation of 2-Phenyl-1butene[END_REF] H. B. Kagan is also recognized for exceptional creativity in the development of an insoluble chiral polymersupported rhodium complex related to the soluble Rh(I)-DIOP complex using a Merrifield resin. [START_REF] Dumont | Asymmetric Catalytic Reduction with Transition Metal Complexes. II Asymmetric Catalysis by a Supported Chiral Rhodium Complex[END_REF] The phosphinated resin obtained from P(C 6 H 5 ) 2 Li was stirred for 21 h under argon at room temperature in a solution of [RhCl(C 2 H 4 ) 2 ] 2 in benzene to provide the insoluble complex, suspended in benzene, which enabled the catalytic heterogeneous asymmetric hydrogenation of αethylstyrene and methylatropate, albeit with a lower efficiency than in solution. As a demonstration of its significance, the publication highlighting this magnificent discovery has been cited over 310 times.

With the idea of avoiding the use of a polystyrene support sensitive to solvent effects and to use a rigid and solventinsensitive surface, Professor Kagan and his group in collaboration with R. Setton at the University of Orléans reported the first graphite-supported chiral catalyst used in the enantioselective hydrogenation of (Z)-PhCH=C(NHAc)COOH to afford (S)-N-acetyl phenylalanine having the configuration opposite to that observed in the Rh-catalyzed homogeneous hydrogenation using (-)-DIOP as ligand, albeit with low enantioselectivities. Nevertheless, the enantioinductions obtained clearly demonstrated that graphite functionalized with a chiral diphosphine was developed for the first time. [START_REF] Kagan | A graphite supported chiral catalyst[END_REF] Next to early ligand developments and their applications in asymmetric hydrogenation, the Kagan group studied the mechanism of the Rh-catalyzed reduction of (E,Z)-αacylaminocinnamic acids [START_REF] Detellier | Asymmetric Catalysis with Chiral Complexes of Rhodium-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane 6. On the Mechanism of Reduction of (E,Z)--Acylaminocinnamic Acids with Homogeneous Rhodium Catalysts[END_REF] with important mechanistic implications and conclusions. The stereochemistry of various α-acylaminocinnamic acids was studied in the presence of the Rh-DIOP complex. Deuterium was used to investigate E-Z isomerization during the catalytic process. Catalytic deuteration of the Z isomer indicated a cisaddition, although the E isomer led to a mixture of d 2 diastereoisomers, demonstrating that some E-Z isomerization occurred prior to the reduction. The Z isomer is reduced much faster than the E isomer. Some E-Z isomerization occurred when the E isomer was reduced, indicated by the fact that there was no incorporation of deuterium at the vinylic position in the presence of the Rh-DIOP catalyst. Knowles at Monsanto independently reported similar mechanism studies. [START_REF] Koenig | Use of Deuterium to Investigate E-Z Isomerisations during Rhodium-Catalyzed Reduction. Asymmetric Induction and Mechanistic Implications[END_REF] In addition to asymmetric hydrogenations, Kagan and his group investigated enantioselective hydrosilylations, which provides access to chiral amines and alcohols as well. After the pioneering examples of homogeneous hydrosilylation of olefins catalyzed by Ni(I) and Pt(II) complexes (albeit with low enantioselectivities), 50 , 51 Ojima and Kagan developed in 1973 the Rh-catalyzed hydrosilylation of ketones. [START_REF] Ojima | Asymmetric Reduction of Ketones via Hydrosilylation Catalyzed by a Rhodium(I) Complex with Chiral Phosphine Ligands[END_REF][START_REF] Poulin | Préparation d'une Diphosphine Chirale liée à une résine Polystyrène Insoluble[END_REF] Specifically, the Rh-DIOP-catalyzed homogeneous and heterogeneous hydrosilylation of acetophenone was carried out using phenylnaphthylsilane, with 58% ee. [START_REF] Dumont | Asymmetric Catalytic Reduction with Transition Metal Complexes. II Asymmetric Catalysis by a Supported Chiral Rhodium Complex[END_REF] As part as his outstanding discoveries, Professor Kagan, in collaboration with R. Setton, was the first to develop the asymmetric hydrosilylation of ketones by a graphite-supported catalyst with configurations opposite to that observed for the less-enantioselective homogeneous hydrogenation. [START_REF] Dumont | Asymmetric Catalytic Reduction with Transition Metal Complexes. II Asymmetric Catalysis by a Supported Chiral Rhodium Complex[END_REF][START_REF] Kagan | A graphite supported chiral catalyst[END_REF] He also carried out unprecedented studies on the Rh-DIOPcatalyzed hydrosilylation of imines, demonstrating that the reactions were at this time more efficient compared to the related ketones, [START_REF] Langlois | Synthèse Asymétrique d'Amines par Hydrosilylation d'Imines Catalysée par un Complexe Chiral de Rhodium[END_REF] and found that the enantioinductions strongly depended on the nature of the silane used for the transformations. The process proceeded effectively under very mild conditions, generating an enormous interest in this method. Finally, H. B. Kagan and his co-workers published many influential reviews and chapters [START_REF] Kagan | Asymmetric Synthesis using Organometallic Catalysts[END_REF] involving asymmetric hydrogenation [START_REF] Kagan | Asymmetric hydrogenation with chiral rhodium complexes: synthetic aspects and stereochemical problems[END_REF][START_REF] Kagan | Asymmetric Catalysis in Organic Synthesis with Industrial Perspectives[END_REF][START_REF] Kagan | Development of Asymmetric Catalysis by Chiral Metal Complexes: the Example of Asymmetric Hydrogenation[END_REF] and hydrosilylation. [START_REF] Kagan | Inorganic Compounds with Unusual Properties II[END_REF][START_REF] Peyronel | Asymmetric Hydrosilylation of Ketones Catalysed by Chiral Rhodium Complexes[END_REF] Professor Henri Kagan is recognized for his exceptional creativity, making outstanding contributions to the field of asymmetric hydrogenation. The concept of C 2 symmetric bidentate diphosphines, with the first report of the DIOP ligand, [START_REF] Kagan | In Encyclopedia of Reagents for Organic Synthesis[END_REF] has inspired numerous chemists with a major influence on the development of asymmetric catalysis as demonstrated by noting that over 460 publications have appeared that include DIOP both in the titles and abstracts. Moreover, 14 patents related to DIOP and their derivatives have been filed by universities and companies (e.g., Mitsubishi Chem Corp, Johnson Matthey, Ajinomoto). Through these many contributions, Professor Kagan has left a legacy of unmatched excellence and scientific impact.

Contributions to Asymmetric Oxidation

Professor Kagan was a true polymath, interested in all types of reactivity, and for each of them he was a key player in major discoveries: this is also the case for asymmetric oxidation reactions.

From the very outset of his career, Professor Kagan was always interested in oxidation reactions, beginning as a PhD student investigating steroid synthesis with Pr Jean Jacques at the Collège de France. As mentioned previously, his first foray into asymmetric oxidative catalysis was the photocyclization reaction induced by circularly polarized light he described in 1971. 7a Albeit with low optical activities, an enantioenriched hexahelicene was isolated in high yield by this method.

Combining his interest in lanthanide chemistry, his laboratory reported the catalytic oxidation of benzoins to benzils with lanthanide nitrates in 1975, [START_REF] Gerard | Lanthanide Reagents in Organic Chemistry. Convenient Catalytic Oxidation of Benzoins to Benzils using Lanthanum Nitrates[END_REF] and also the efficient employment of lanthanide alkoxides in the catalytic epoxidation of allylic alcohols and in Meerwein-Ponndorf-Verley-Oppenauer reactions. [START_REF] Lebrun | A New Preparation of Lanthanide Alkoxides, and some Applications in Catalysis[END_REF] He even explored heterogeneous catalysis by treating the cheapest source of Ce(IV), cerium dioxide, with a catalytic quantity of ruthenium chloride; the resulting CeO 2 -Ru system promoted the efficient dioxygen oxidation of various alcohols and aldehydes, with the targeted products easily isolated by filtration and the heterogeneous catalyst regenerated in the presence of water and formaldehyde. [START_REF] Vocanson | Dioxygen Oxidation of Alcohols and Aldehydes over a Cerium Dioxide-Ruthenium System[END_REF] Professor Kagan's seminal contributions in the field of asymmetric oxidation are indisputable. Together with Volker Schurig in Tübigen and Hubert Mimoun at the Institut Français du Pétrole, Henri Kagan first investigated this domain in 1979, at a time when the area was still in its infancy even for the oxidation of activated carboncarbon double bonds. He and his collaborators indeed described the use of an optically active molybdenum(VI) peroxo complex from an (S)-N,N-dimethyllactamide ligand to produce enantioenriched epoxides from simple unfunctionalized olefins in up to 34 % ee. [START_REF] Kagan | Asymmetric Epoxidation of Simple Olefins with an Optically Active Molybednum(VI) Peroxo Complex[END_REF] In 1980, Katsuki and Sharpless reported their impressive epoxidation system [Ti(OiPr) 4 , enantiopure diethyl tartrate (DET), and tert-butyl hydroperoxide (TBHP)], yielding highly enantioenriched 2,3-epoxy alcohols from allylic alcohols. [START_REF] Katsuki | The First Practical Method for Asymmetric Epoxidation[END_REF] Only a few years later, Kagan's group pointed out that although highly valuable building blocks, practical access to scalemic sulfoxides was still in demand by purely chemical oxidants. With Philippe Pitchen, he discovered that the addition of a molar equivalent of water to the Sharpless reagent led to the oxidation of sulfides to enantioenriched sulfoxides, whereas in the absence of water the reaction remained non-selective (Figure 14). [START_REF] Pitchen | An efficient Asymmetric Oxidation of Sulfides to Sulfoxides[END_REF] This discovery is the result of a sharp optimization of the different parameters of the reaction, the quantity of the reagents, and their involvement in the mechanism of this oxidation. [START_REF] Pitchen | An Efficient Asymmetric Oxidation of Sulfides to Sulfoxides[END_REF]

Figure 14. Asymmetric oxidation of sulfides to sulfoxides

Indeed, the best sulfide oxidation system involved the use of two equivalents of DET per titanium, and one equivalent of water, the absence of the latter or its presence in excess (i.e., 6 equivalents) leading to racemic sulfoxides. At that time, infrared spectroscopic analyses led to the conclusion that similar oxidizing reagents arose from the 1:1:1 or 1:2:0 (Ti/DET/H 2 O) stoichiometry; the Kagan group hypothesized that hydrolysis of the Ti-O-iPr bonds formed species with μ-oxo bridges, leading to a polymeric active species. Hammett correlation measurements were performed to propose two mechanistic pathways for the reaction, i.e., an external attack by the chiral active species on the sulfur, or prior coordination of sulfur to titanium before the oxidation. He even proposed that one or the other of these mechanisms were at play depending on the temperature at which the reaction was carried out. The usual thorough and meticulous work of Professor Kagan is still obvious in this study in which he furthermore proposed a model to predict the absolute configuration of the formed sulfoxides and argued about inhibition effect of sulfoxides. It is so pleasant to read in these founding papers that Professor Kagan mentions in the acknowledgment part of the personal exchanges with Pr Sharpless on this subject; he also added an addendum to his 1984 article, pointing out that a similar study was published by Seraglia in Italy, just after the Tetrahedron Letters 67 preliminary account appeared. [START_REF] Di Furia | Synthesis of Chiral Sulfoxides by Metal-Catalyzed Oxidation with t-Butyl Hydroperoxides[END_REF] The Kagan group went further on to optimize and study in detail this efficient enantioselective transformation toward valuable sulfoxide derivatives. [START_REF] Zhao | Asymmetric Oxidation of Sulfides Mediated by Chiral Titanium Complexes: Mechanistic and Synthetic Aspects[END_REF] Although he clarified the role of water on reactivity, he also studied the influence of the nature of the oxidant and discovered the beneficial use of cumene hydroperoxide on both the yield and the enantioselectivity values for many sulfoxides. At that time, he and his group furthermore demonstrated that the reaction could be performed with a catalytic quantity of the oxidation mixture, in the presence of molecular sieves, without decreasing its activity, albeit with a loss in its selectivity. His charming stubbornness in providing extremely reproducible protocols is evidenced in a 1995 paper [START_REF] Brunel | Highly Enantioselective Oxidation of Sulfides Mediated by a Chiral Titanium Complex[END_REF] in which one can read the perfect description of the procedure in terms of catalyst preparation, temperature, reaction time, order of addition, source of reagents, time, and storage conditions, etc. This allowed the synthesis of chiral sulfoxides with excellent enantiomeric excesses in a perfectly reproducible way, which is indisputable knowing that this article has been cited more than 170 times! This precision in his way of carrying out his research enabled him to optimize at the same time the asymmetric oxidation process involving only catalytic quantities of the oxidizing system. [START_REF] Brunel | Catalytic Asymmetric Oxidation of Sulfides with High Enantioselectivities[END_REF] The replacement of water by 2propanol in combination with cumyl hydroperoxide allowed indeed the successful oxidation under catalytic conditions. A careful optimization of all reaction parameters led both to high yield and high ee for a wide range of aryl-, alkyl-or dialkylsulfides, provided one used a combination Ti(Oi-Pr) 4 /DET/i-PrOH with the exact 1:4:4 proportion in the presence of molecular sieves in an equivalent weight with respect to the sulfide (Figure 15). Enantiomeric excesses of more than 95% were measured, being the highest enantioselectivities achieved at that time in catalytic asymmetric sulfoxidations by nonenzymatic methods.

Figure 15. Catalytic asymmetric oxidation of sulfides to sulfoxides

Pr Kagan very originally employed his method for the enantioselective oxidation of 1,3-dithianes [START_REF] Samuel | Asymmetric Oxidation of some 1,3-Dithianes in presence of Chiral Titanium Complexes[END_REF] and for the synthesis of new optically active sulfoxides with chelating properties, in particular enantioenriched 8-(methylsulfinyl)-quinoline. [START_REF] Baldenius | Synthesis of New Optically Active Sulfoxides with Chelating Properties[END_REF] In collaboration with industrial groups, Pr Kagan has proven the robustness of this method; the catalytic system was slightly modified with the use of an enantiopure amino alcohol as chiral ligand but led to the production of almost enantiomerically pure tenatoprazole, an irreversible proton pump inhibitor used for the prevention and treatment of gastric acid-related diseases (Figure 16). [START_REF] Delamare | A New Titanate/(+)-(1R,2S)cis-1-Amino-2-Indanol System for the Asymmetric Synthesis of (S)-Tenatoprazole[END_REF] This procedure was successfully implemented on scales reaching multiple kilograms.

Figure 16. Asymmetric synthesis of (S)-tenatoprazole

A major application of this procedure has undoubtedly been its ability to yield ferrocenyl sulfoxides with high enantiomeric purity. [START_REF] Diter | Highly Enantioselective Oxidation of Ferrocenyl Sulfides[END_REF] Again for these specific substrates, the method of preparation of the oxidant was carefully studied for a well-defined stoichiometry to achieve virtually complete enantioselectivity in the case of some ferrocenyl aryl sulfides. These derivatives have served as valuable building blocks for their highly diastereoselective ortho-lithiation toward the synthesis of ferrocenyl derivatives with planar chirality. [START_REF] Rebière | Asymmetric synthesis and highly diasteroselective ortholithiation of ferrocenyl sulfoxides. Application to the synthesis of ferrocenyl derivatives with planar chirality[END_REF] It is precisely by using this enantioselective oxidation reaction that the Kagan group investigated the question of understanding the influence of the enantiomeric excess of the catalyst used on the asymmetric induction that it produces. [START_REF] Puchot | Nonlinear Effects in Asymmetric Synthesis. Examples in Asymmetric Oxidations and Aldolization Reactions[END_REF][START_REF] Brunel | Nonlinear effects as 'indicators' in the tuning of asymmetric catalysts[END_REF] This is another major discovery and advancement arising from the Kagan laboratory that is detailed elsewhere in this contribution.

Oxidation, and in particular asymmetric oxidation, are fields that Professor Kagan was able to lead so well with modesty, and in which one can only note the impressive results obtained. 79 , 80 His contributions come from an unfailing curiosity endowed with a creativity as rare as it is productive and a meticulousness in the exploration of reactivities that must remain inspiring for the community of asymmetric catalysis.

Contributions to Lanthanide Chemistry

It is not at all obvious what sparked Professor Kagan's interest in lanthanide chemistry, but as with all the research he spearheaded, he was a true pioneer whose creative genius, instincts, and original thinking sparked a revolution in this domain. Thus, prior to the Kagan group's investigations, it is safe to say (as pointed out by Kagan himself) that the only interest shown by most organic chemists in lanthanides was the use of Ce(IV) reagents as oxidants or the role played by various lanthanide complexes as chiral shift reagents.

The first contribution to lanthanide chemistry from the Kagan Laboratory appears to be a report on the use of lanthanide nitrates for the catalytic oxidation of benzoins to benzils. [START_REF] Gerard | Lanthanide Reagents in Organic Chemistry. Convenient Catalytic Oxidation of Benzoins to Benzils using Lanthanum Nitrates[END_REF] In this brief communication, five different lanthanide nitrates (Ln = La, Sm, Eu, Tm, Yb) were used in the conversion of several substituted benzoins to benzils. Ytterbium nitrate was determined to be the most efficient catalyst in a process that was proposed to involve NO 3 -as the oxidizing agent, with oxygen serving as the stoichiometric oxidant (Figure 17). The concluding statement of the contribution presciently proclaimed, "We are currently carrying out further studies of lanthanum salts as catalysts or modifiers for organic reactions since many are relatively cheap and safe reagents".

Figure 17. Oxidation of benzoins to benzils with lanthanide chemistry

This exploration thus led to forays into other catalytic redox processes using various lanthanide complexes. For example, a serendipitous observation during the course of the group's investigations on SmI 2 chemistry (vide infra) led to a study on the preparation of lanthanide alkoxides and their use as catalysts in Meerwein-Ponndorf-Verley-Oppenauer reactions (Figure 18). [START_REF] Namy | New Preparations of Lanthanide Alkoxides and Their Catalytical Activity in Meerwein-Ponndorf-Verley-Oppenauer Reactions[END_REF] Thus, Barbier-type reactions of SmI 2 with various organic halides and aldehydes led to a class of samarium alkoxides that were found to participate in Oppenauer-type reactions with the aldehydes. The group followed up on this chemistry by developing a convenient synthesis of various lanthanide alkoxides and studying their role in the reversible hydride transfer processes between alcohol and carbonyl substrates. Further studies led to a convenient synthesis of Ln(Oi-Pr) 3 complexes (Ln = La, Ce, Sm, Yb) and their use in the catalytic epoxidation of allylic alcohols (Figure 19). Beyond the use of various lanthanide complexes in oxidation/reduction chemistry, the Lewis acid character of diverse lanthanide salts was exploited by the Kagan group in several domains. Among the first such studies, the selective rearrangement of terminal epoxides to methyl ketones was explored (Figure 20). [START_REF] Prandi | Selective Catalyzed-Rearrangement of Terminal Epoxides to Methyl Ketones[END_REF] Serendipity again appears to have played a role in the discovery of this transformation, because in the exploration of the deoxygenation of epoxides by SmI 2 (vide infra), terminal epoxides unexpectedly provided methyl ketones as byproducts. Preparations of various iodo-containing samarium alkoxides were subsequently found to lead to excellent yields of the corresponding methyl ketones by a unique mechanism, a process that provided a convenient two-step (epoxidation/rearrangement) access to methyl ketones from terminal alkenes.

Figure 20. Selective rearrangement of terminal epoxides to methyl ketones

The Lewis acid character of lanthanide salts was exploited in other reactions of epoxides. For example, in the presence of thiols, various lanthanide complexes catalyzed the ring-opening of epoxides to generate α-hydroxy thioethers. [START_REF] Vougioukas | Oxirane Ring Opening Reactions with Thiols Catalyzed by Lanthanide Complexes[END_REF] The method developed represented a very mild approach to the synthesis of such substructures (Figure 21). In addition to epoxides, lanthanide(III) chlorides as well as other complexes were found to serve as excellent Lewis acids for several carbonyl group transformations, including the promotion of aldol reactions with silyl enol ethers and addition of Me 3 SiCN to aldehydes, forming cyanohydrin derivatives. [START_REF] Vougioukas | Lanthanides as Lewis-Acid Catalysts in Aldol Addition, Cyanohydrin-Forming and Oxirane Ring Opening Reactions[END_REF]

Figure 22. Aldol reactions with silyl enol ethers and addition of Me 3 SiCN to aldehydes

As relatively mild Lewis acids, various Ln(III) salts were also found to induce ether-and thioether formation from allylic alcohol precursors. [START_REF] Ouertani | Ether Formation from Allylic Alcohols by Samarium Trichloride[END_REF]

Figure 23. Thioether formation from allylic alcohol precursors

Although simple in concept, design, and execution, these studies on the use of lanthanide complexes in catalysis provided the inspiration for others to delve into the potential of lanthanide catalysts for myriad transformations, including Diels-Alder reactions, Friedel-Crafts reactions, and beyond.

As important as Professor Kagan's contributions to lanthanide catalysis were to awaken the organic chemistry community to this field of research, it must be said that his single most remarkable contribution to lanthanide chemistry was the introduction and development of samarium diiodide (SmI 2 ). The initial incursion into this research was extremely unassuming, being revealed in a contribution describing a new and convenient synthesis of SmI 2 and YbI 2 (by the reaction of Sm or Yb metal with 1,2-diidodoethane), along with several seminal reactions using these reagents (e.g., reduction of conjugated carbonyl substrates, reduction of aldehydes and ketones, and the initial Barbier-type reactions). [START_REF] Namy | A New Preparation of Some Divalent Lanthanide Iodides and their Usefulness in Organic Synthesis[END_REF] Samarium diiodide had first appeared in the literature in 1930, [START_REF] Jantsch | Thermal Decomposition of Rare Earth Halides[END_REF] but received scant attention. The reasons were obvious -there was no practical synthesis of the material, and no one previously had the foresight to recognize that it could be useful in any way for organic synthesis. Consequently, the reagent languished away from the eyes of organic chemists for five decades, with less than a dozen mentions in the scientific All of changed in 1977 with the first report from the Kagan laboratory on the synthesis and utility of samarium diiodide (SmI 2 ) as a one-electron reducing agent.

Although exceedingly important as the ground-breaking report of viable and convenient SmI 2 chemistry, this Nouveau Journal de Chimie communication paled in comparison to the blockbuster paper that followed in the Journal of the American Chemical Society three years later, where the full scope of the processes outlined above were detailed. [START_REF] Girard | Divalent Lanthanide Derivatives in Organic Synthesis. 1. Mild Preparation of Samarium Iodide and Ytterbium Iodide and their Use as Reducing or Coupling Agents[END_REF] In this epic contribution, the Kagan group outlined a series of transformations that set the stage for all SmI 2 chemistry to follow (Figure 24). Through this initial research, the power of SmI 2 to carry out essential reductions and reductive coupling reactions was revealed -a virtual cornucopia of transformations. Deoxygenation reactions of both epoxides and sulfoxides were described, most with very high yields. The reduction of conjugated carbonyl substrates demonstrated that while α,βunsaturated carboxylic acids and -esters could be cleanly converted to their saturated congener, unsaturated aldehydes and -ketones were problematic owing to competitive over-reduction. As expected based on these results, isolated aldehydes and ketones were cleanly reduced to the corresponding alcohols, while carboxylic acids andesters were unreactive. Aldehydes could be reduced with excellent chemoselectivity in the presence of ketones. Alkyl iodides, -bromides, and even -tosylates were reduced to the corresponding alkanes, but perhaps most importantly, the group demonstrated that SmI 2 -promoted Barbier-type reactions could be carried out in exceptionally high yields.

Figure 24. Key transformations discovered in Kagan's seminal SmI 2 methods paper

As a demonstration of its significance, the article outlining these results has now been viewed over 10,000 times and cited over 1,300 times, and although virtually no research on SmI 2 was published during the first fifty years of its initial description, now nearly 2000 papers describing various aspects of SmI 2 have been published, speaking volumes about the profound influence of this contribution.

The Kagan group would go on to explore other important aspects of synthetic chemistry related to SmI 2 . For example, the use of this reagent for the formation of pinacols from both aldehydes and ketones was outlined. [START_REF] Namy | Efficient Formation of Pinacols from Aldehydes or Ketones Mediated by Samarium Diiodide[END_REF] The remarkable rapidity of this reaction with aromatic aldehydes and its toleration of relatively sensitive functional groups (e.g., nitro and cyano) made it a useful addition to the synthetic organic chemistry toolbox.

Figure 25. Formation of pinacols

In a somewhat related contribution, the group discovered that α-ketols could be generated from the reaction of acid chlorides and SmI 2 or dicyclopentadienylsamarium (Cp 2 Sm). [START_REF] Collin | Synthesis of -Ketols Mediated by Divalent Samarium Compounds[END_REF] Aromatic acid chlorides were found to provide clean conversion to symmetrical α-diketones in the presence of these reducing agents, while aliphatic acid chlorides provided reasonable yields of α-ketols in the presence of either ketones or aliphatic and aromatic aldehydes. Mechanistic investigations indicated that the acyl chlorides reacted with the Sm(II) species to generate the unusual acylsamarium(III) intermediates, which subsequently underwent addition to the carbonyl electrophiles to generate the observed products. A later investigation revealed that these transformations were best carried out in THP rather than THF, [START_REF] Namy | Samarium Diiodide in Tetrahydropyran: Preparation and some Reactions in Organic Chemistry[END_REF] presumably because the former solvent provided greater stabilization of the key acylsamarium intermediate (Figure 26). Getting back to catalysis, the Kagan group discovered that many of the protocols outlined above for stoichiometric SmI 2 chemistry were improved upon by using various transition metal catalysts. [START_REF] Machrouhi | Improved Reactivity of Diiodosamarium by Catalysis with Transition Metal Salts[END_REF] Thus, Barbier-type reactions, deoxygenation of epoxides, reduction of ketones, and the generation of α-ketols by reaction of acid chlorides with nitriles all benefitted in terms of yield and rate of reactions in the presence of catalytic NiI 2 .

At this point in time, than 45 years after the first report from the group at Orsay, applications of lanthanides to challenges in organic synthesis continue unabated, and they range from attempts to develop catalytic transformations of Sm(II) species [START_REF] Flowers | Samarium-Mediated Reductions[END_REF] to the burgeoning area of photoredox chemistry. [START_REF] Qiao | Lanthanide Photocatalysis[END_REF] Nearly all of this activity can be ultimately traced directly back to the profound vision and commanding intellect of its progenitor, Professor Henri Kagan.

Contributions to Nonlinear Effects in Asymmetric Catalysis

The beauty of chemistry is that an accident can provide mankind with new knowledge and breakthrough technologies. A scientist who painstakingly conducts an experiment and carefully analyzes its results can change the world. At the same time, there are discoveries in chemistry that are difficult to make by chance and require a genius mind. Such discoveries include nonlinear effects in asymmetric catalysis (Figure 27). Anticipating, understanding, explaining, and at the same time finding experimental evidence yourself is an extremely rare example. In the late 1960s, when Professor Kagan became involved in asymmetric synthesis, he wondered about the mechanisms and possibility of nonlinear effects. At that time there were very few enantiomeric pure ligands. The ones on which he was able to test such an effect were not observed. [START_REF] Kagan | Nonlinear Effects in Asymmetric Catalysis: A Personal Account[END_REF] However, he, understanding the importance of the possibility of the existence of nonlinear effects, did not give up and kept looking. Almost two decades later, his first article proving the existence of nonlinear effects was published. The first paper was published in 1986 and immediately included not only a conjecture, but also three fundamentally different examples and even an explanation of the phenomenon. [START_REF] Puchot | Nonlinear Effects in Asymmetric Synthesis. Examples in Asymmetric Oxidations and Aldolization Reactions[END_REF] As we can see in many of Professor Kagan's discoveries there is a trend to show the breadth of the idea by fundamentally different examples at once.

In his first paper, Professor Kagan posed the question: 'what is the correlation between the enantiomeric excess (ee) of a compound and the value of one of its chemical properties?'

Thus, the authors were able to show that the oxidation of asymmetric sulfide with tert-butyl hydroperoxide using diethyl tartrate and tetraisopropoxide produced enantiomerically enriched sulfoxide (Figure 28). A negative nonlinear effect was observed for such a system. This is because a dimeric complex consisting of two ligands and two titanium atoms is formed in the system. When using a mixture of ligand enantiomers in a ratio other than 50 to 50 or 100 to 0, combinations of RR, RS, SR, SS pairs can be formed. The RR vs RS pairs are diastereomers and can exhibit different reaction rates as well as different enantioselectivities in the reaction. In this case, the pair that loses in enantioselectivity wins in terms of reaction rate. This results in a negative nonlinear effect.

Figure 28. The first example of negative nonlinear effect

As a second example, the authors used the same oxidation system, but for geraniol. It seemed counterintuitive to expect the opposite situation for this case. However, a positive nonlinear effect is observed here (Figure 29).

Figure 29. The first example of positive nonlinear effect

As a third example, the authors described the asymmetric intramolecular Hajos-Parrish-Eder-Sauer-Wiechert reaction (Figure 30). The authors found a small negative nonlinear effect. Later, when the era of asymmetric organocatalysis began, it became an urgent task to understand the mechanism regarding the presence of nonlinear effects in the aldol reaction catalyzed by proline and its analogues. This case turned out to be very interesting because the possibility of a solid/liquid equilibrium turned out to be an essential factor. What did the discovery of nonlinear effects in asymmetric catalysis lead to? A better understanding of what happens in asymmetric reactions. With a few simple experiments of mixing two enantiomers of a ligand or precatalyst, it became possible to obtain data on the structure of the active catalyst -a species that may be generated in such low concentration or so unstable that it is not possible to isolate.

The study of nonlinear effects made it possible to show the possibility of a reaction explaining the origin of chirality. Kagan's original work led to a flurry of work on the search for nonlinear effects. In 1988, Oguni showed a positive nonlinear effect in the reaction of the addition of diethylzinc to benzaldehyde (Figure 31). [START_REF] Oguni | Asymmetric Amplifying Phenomena in Enantioselective Addition of Diethylzinc to Benzaldehyde[END_REF] In 1989, Noyori showed that in this reaction, the use of the ligand DAIB with an enantiomeric excess of only 15% allows access to a product with 95% ee (Figure 32). [START_REF] Kitamura | Enantioselective Addition of Dialkylzincs to Aldehydes Promoted by Chiral Amino Alcohols. Mechanism and Nonlinear Effect[END_REF] This allowed Soai to discover his famous asymmetric self-catalytic reaction (Figure 33). Many attempts to engage in asymmetric catalysis resulted in a product with a low enantiomeric excess using an enantiomeric pure catalyst. Who would have thought that the situation could be the opposite, that an impure substance could give an enantiomeric excess in a product exceeding its own purity? Henri Kagan was able not only to conceive of this concept, but also to find evidence for its existence.

Here we have considered only giant milestones in Professor Kagan's work. The fields of his interests were very diverse. He was involved in heterogeneous asymmetric catalysis, [START_REF] Dumont | Asymmetric Catalytic Reduction with Transition Metal Complexes. II Asymmetric Catalysis by a Supported Chiral Rhodium Complex[END_REF] light energy storage in chemical systems (Figure 34), 11b selective fluorination with such amazing reagents as C 19 XeF 6 (Figure 35), [START_REF] Bertin | Graphite electrolytic lamellar reagents in organic chemistry. Esterifications in the presence of graphite bisulfate[END_REF] asymmetric phase transfer catalysis, and chiral shift reagents (Figure 36) [START_REF] Deshmukh | A Convenient Family of Chiral Shift Reagents for Measurement of Enantiomeric Excesses of Sulfoxides[END_REF] .

Conclusion

As is clear from the brief descriptions above outlining Professor Kagan's exceptional contributions to science, he was a gifted and extraordinarily creative individual with exceedingly broad interests, and possessed a deep intellect and innate curiosity that allowed him to make those types of leaps of knowledge that allow one to consider him a true genius. Modern metrics, e.g., citations, hindex, etc., cannot begin to capture his influence in chemistry -he established several entirely new fields of research that became pillars upon which substantial realms of exploration are now based.

From a personal point of view, those who know him recognize him as a quiet, thoughtful, caring, and self-effacing individual, not at all interested in self-promotion or hyping his remarkable contributions. In this, he truly deserves tremendous respect and admiration.

Figure 1 .Figure 2 .

 12 Figure 1. Title page of Henri Kagan's Ph.D. thesis

Figure 6 .

 6 Figure 6. First diphosphines with C2-symmetry

Figure 7 .Figure 8 .

 78 Figure 7. Samples of DIOP that were synthesized in Professor Kagan's laboratory and are preserved to this day in Professor Kagan's office

63

 63

Figure 18 .Figure 19 .

 1819 Figure 18. Lanthanide alkoxides and their use as catalysts in Meerwein-Ponndorf-Verley-Oppenauer reactions

Figure 21 .

 21 Figure 21. Ring-opening of epoxides with thiols.

Figure 26 .

 26 Figure 26. Synthesis of α-hydroxy carbonyl compounds.

Figure 27 .

 27 Figure 27. Linear and nonlinear effects in asymmetric catalysis.

Figure 30 .

 30 Figure 30. Possible mechanism for the Hajos-Parrish-Eder-Sauer-Wiechert reaction proposed in 1986.

98

 98

Figure 31 .

 31 Figure 31. A positive nonlinear effect in the reaction of the addition of diethylzinc to benzaldehyde showed by Oguni et al.

Figure 32 .

 32 Figure 32. A positive nonlinear effect in the reaction of the addition of diethylzinc to benzaldehyde shown by Noyori et al.

Figure 33 .

 33 Figure 33. Asymmetric self-catalytic reaction shown by Soai et al.

Figure 34 .Figure 35 . 6 Figure 36 .

 3435636 Figure 34. Light energy storage in chemical systems

ORCID

Denis Chusov: 0000-0001-6770-5484 Gary A. Molander: 0000-0002-9114-5584 Virginie Ratovelomanana-Vidal: 0000-0003-1167-1195 Olivier Riant: 0000-0003-4852-6469 Emmanuelle Schulz: 0000-0002-0844-8825

Funding Sources

The authors are grateful for the financial support provided by the CNRS, the Ministère de l'Enseignement Supérieur and the French National Research Agency and Charm3At LabEx (ANR-11-LABEX-0039, ANR-21-CE07-0038-02 and ANR-21-CE07-0034-02) and industrial partners. The authors are grateful for the financial support provided by NIGMS (R35 GM 131680 to G.A.M.). The authors are grateful for the financial support from Ministry of Science and Higher Education of the Russian Federation (Contract No. 075-03-2023-642).

AUTHOR INFORMATION Corresponding Authors

Denis Chusov -denis.chusov@gmail.com Gary A. Molander -gmolandr@sas.upenn.edu Virginie Ratovelomanana-Vidal -virginie.vidal@chimieparistech.psl.eu Olivier Riant -olivier.riant@uclouvain.be Emmanuelle Schulz -emmanuelle.schulz@universite-parissaclay.fr