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The Tateshina conference celebrates its 20th anniversary this year. Its founder, Eiichi Nakamura, modeled the conference after the Burgenstock conference where he was a speaker in April 2000. This short account highlights this event.

Mono- and multinuclear complexes of ruthenium and [n]cycloparaphenylene (CPP, n = 5 and 6) were synthesized in excellent yields through ligand exchange of the cationic complex [(Cp)Ru(CH3CN)3](PF6) with CPP. In the multinuclear complexes, ruthenium selectively coordinated to alternate paraphenylene units to give bis- and tris-coordinated Ru complexes for [5] and [6]CPPs, respectively. Single-crystal X-ray analysis revealed the Ru was coordinated with η(6)-hapticity on the convex surface of CPP.

Highly tuned, one-point binding chiral iron and ruthenium complexes selectively coordinate and activate α,β-unsaturated aldehydes and ketones toward asymmetric catalytic Diels-Alder cycloaddition reactions. Here we focus on the application of these transition-metal Lewis acids to asymmetric catalytic 1,3-dipolar cycloaddition reaction between enals and cyclic and acyclic nitrones as well as aryl nitrile oxides to give isoxazolidines and isoxazolines, respectively.

This article describes the situation of Department of Organic Chemistry in the year of the 450th anniversary of the University of Geneva.

Details of the direct synthesis of cationic Ru(II)(η5‐Cp)(η6‐arene) complexes from ruthenocene using microwave heating are reported. Developed for the important catalyst precursor [Ru(II)(η5‐Cp)(η6‐1‐4,4a,8a‐naphthalene)][PF6] reaction time could be shortened from three days to 15 min. The method was extended to [Ru(II)(η6‐benzene)(η5‐Cp)][PF6], [Ru(II)(η5‐Cp)(η6‐toluene)][PF6], [Ru(II)(η5‐Cp)(η6‐mesitylene)][PF6], [Ru(II)(η5‐Cp)(η6‐hexamethylbenzene)][PF6], [Ru(II)(η5Cp)(η6‐indane)][PF6], [Ru(II)(η5‐Cp)(η6‐2,6‐dimethylnaphthalene)][PF6], and [Ru(II)(η5‐Cp)(η6‐pyrene)][PF6]. 1‐methylnaphthalene and 2,3‐dimethylnaphthalene afforded mixtures of regioisomeric complexes. [Ru(Cp)(CH3CN)3][PF6], derived from the naphthalene precursor provided access to the cationic RuCp complexes of naphthoquinone, tetralindione, 1,4‐dihydroxynaphthalene, and 1,4‐dimethoxynaphthalene. Reduction of the tetralindione complex afforded selectively the endo,endo diol derivative. X‐Ray structures of five complexes are reported.

PEPPSI complexes incorporating chiral N-heterocyclic carbene (NHC) ligands based on 2,2-dimethyl-1-(o-substituted aryl)propan-1-amines were synthesized. Two complexes, with one saturated and one unsaturated NHC ligand, were structurally characterized. The chiral PEPPSI complexes were used in asymmetric Suzuki–Miyaura reactions, giving atropisomeric biaryl products in modest to good enantiomeric ratios.

Acrolein, methacrolein, methyl vinyl ketone, ethyl vinyl ketone, 3-methyl-3-en-2-one, and divinyl ketone were coordinated to a cationic cyclopentadienyl ruthenium(II) Lewis acid incorporating the electron-poor bidentate BIPHOP–F ligand. Analysis by NOESY and ROESY NMR techniques allowed the determination of conformations of enals and enones present in solution in CD2Cl2. The results were compared to solid-state structures and to the facial selectivities of catalytic asymmetric Diels–Alder reactions with cyclopentadiene. X-Ray structures of four Ru-enal and Ru-enone complexes show the α,β-unsaturated C=O compounds to adopt an anti-s-trans conformation. In solution, enals assume both anti-s-trans and anti-s-cis conformations. An additional conformation, syn-s-trans, is present in enone complexes. Enantioface selectivity in the cycloaddition reactions differs for enals and enones. Reaction products indicate enals to react exclusively in the anti-s-trans conformation, whereas with enones, the major product results from the syn-s-trans conformation. The alkene in s-cis conformations, while present in solution, is shielded and cannot undergo cycloaddition. A syn-s-trans conformation is found in the solid state of the bulky 6,6-dimethyl cyclohexanone-Ru(II) complex. The X-ray structure of divinyl ketone is unique in that the Ru(II) center binds the enone via a η2 bond to one of the alkene moieties. In solution, coordination to Ru–C=O oxygen is adopted. A comparison of facial preference is also made to the corresponding indenyl Lewis acids.

A palladium-catalyzed intramolecular α-arylation of an amide in the presence of a bulky chiral N-heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)-6-chloro-3-(3-chlorobenzyl)-1,3-dihydro-3-(3-methoxyphenyl)-2H-indol-2-one ((R)-5). This oxindole, in racemic form, had been shown previously to be an anticancer agent. (R)-5 was obtained with an overall yield of 45% and with 96% enantioselectivity.

Very high asymmetric inductions result in the Pd-catalyzed intramolecular arylation of amides to give 3,3-disubstituted oxindoles when new in situ-generated chiral N-heterocyclic carbene (NHC*) ligands are employed. Structural studies show that conformational locking to minimize allylic strain is the key to understanding the function of these ligands. New applications of these ligands in the frontier area of asymmetric coupling reactions involving C(sp3)–H bonds are detailed. Highly enantioenriched fused indolines are accessible using either preformed- or in situ-generated Pd-NHC* catalysts. Remarkably, this occurs at high temperature (140–160 °C) via excellent asymmetric recognition of an enantiotopic C–H bond in an unactivated methylene unit.

Well defined, stable, one-point binding ruthenium complexes and selectively bind and activate alpha,beta-unsaturated carbonyl compounds for cycloaddition reactions. These mild Lewis acids catalyze asymmetric 1,4-addition reactions of aryl thiols to enones with product selectivities up to 87% ee. (31)P NMR experiments provide an insight into the intricate equilibria governing the reaction mechanism. The absolute configuration of the major products indicates enones to react in the syn-s-trans orientation. Models based on X-ray structures of the Ru complexes can be used to rationalize selectivity.

An sp(2)/sp(3) get-together: A novel and efficient method can be used to synthesize 3,3-disubstitued oxindoles by the direct intramolecular oxidative coupling of an aryl C(sp(2))-H and a C(sp(3))-H center (see scheme; DMF = N,N-dimethylformamide).

A novel bicyclo[8.3.1]enediyne was readily synthesized by chromium-mediated dearomatization of 2,6-bis(trimethyl­silyl)anisole. The enediyne undergoes Bergman cyclization with a half-life of 14.4 hours at 142 °C.

The highly tuned, one-point binding cationic cyclopentadienyl-iron and -ruthenium complexes 1 and 2 that incorporate chiral bidentate pentafluoroaryl-phosphinite ligands selectively coordinate and activate alpha,beta-unsaturated carbonyl compounds towards asymmetric catalytic cycloaddition reactions with diaryl nitrones. The reaction gives isoxazolidine products in good yields, with complete endo selectivity and high enantioselectivity. The products are obtained as a mixture of regioisomers in ratios varying from 96:4 to 15:85. The regioselectivity correlates directly with the electronic properties of the nitrone. This is shown by the experimental and computational data.

Bring on the big cats: New, C2-symmetric bulky N-heterocyclic carbene ligands bring major improvements in the palladium-catalyzed asymmetric intramolecular α-arylation of amides to give oxindoles (see picture, dba=trans,trans-dibenzylideneacetone), which are formed in high yield and excellent enantiomeric purity.

For 25 years it has been known that 1,4-dihydroxynaphthalene and tetrahydronaphthalene-1,4-dione coexist as stable tautomers; however, the dione has now emerged as an interesting starting material for synthesis. Its efficient isolation is reported, and the corresponding [Cr(CO)3] complexes of the two tautomers are prepared, thus leading to efficient desymmetrization using chiral diamine acyl-transfer catalysts

cis-Fused [6,8], [6,7], [6,6] and [6,5] ring systems containing a cyclohexadiene ring unit, a cycloenone ring and a quaternary carbon at the ring junction were obtained in only two steps from [Cr(CO)3(eta6-p-methoxyphenyl oxazoline)]. The sequence proceeds via diastereoselective addition of three C-substituents across an arene double bond, followed by allylation and ring closing metathesis (RCM). RAMP-hydrazone and (R)-isopropyloxazoline were used as chiral auxiliaries to provide, after removal of the auxiliaries, the enantiomerically highly enriched [6,7] cis-fused system.

An efficient dearomatization process of [Cr(arene)(CO)3] complexes initiated by a nucleophilic acetaldehyde equivalent is detailed. It generates in a one-pot reaction three C--C bonds and two stereogenic centers. This process allowed a rapid assembly of a cis-decalin ring system incorporating a homoannular diene unit in just two steps starting from aromatic precursors (Scheme 2). The method was applied to the total synthesis of the eudesmane-type marine furanosesquiterpene (±)-15-acetoxytubipofuran (2). Two routes were successfully used to synthesize the ?-lactone precursor of the furan ring. The key step in the first approach was a Pd-catalyzed allylic substitution (Scheme 3), while in the second approach, an Eschenmoser-Claisen rearrangement was highly successful (Scheme 4). The Pd-catalyzed allylic substitution could be directed to give either the (normal) product with overall retention as major diastereoisomer or the unusual product with inversion of configuration (see Table). For the synthesis of the (-)-enantiomer (R,R)-2 of 15-acetoxytubipofuran, an enantioselective dearomatization in the presence of a chiral diether ligand was implemented (Scheme 7), while the (+)-enantiomer (S,S)-2 was obtained via a diastereoselective dearomatization of an arene-bound chiral imine auxiliary (Scheme 8). Chiroptical data suggest that a revision of the previously assigned absolute configuration of the natural product is required.

[Ru(η5-C5H5)(CH3CN)3][PF6] (1), a versatile precursor to catalysts containing the CpRu+ complex fragment, can be obtained in high yield via Cp/naphthalene exchange in ruthenocene. This new route via the complex [RuCp(naphthalene)][PF6] (4) avoids both highly toxic thallium reagents and the need for a photoreactor.

The C2-sym. electron-poor ligand (R)-BINOP-F (4; (R)-2,2'-[bis(pentafluorophenyl)phosphinoxy]-1,1'-binaphthalene) was prepd. by reaction of (R)-BINOL ((R)-1,1'-binaphthalene-2,2'-diol) with bromobis(pentafluorophenyl)phosphine in the presence of NEt3. The iodo complex [CpRu((R)-BINOP-F)(I)] ((R)-6) was obtained by substitution of two carbonyl ligands by (R)-4 in the in situ-prepd. [CpRu(CO)2H] complex followed by reaction with iodoform. Complex 6 was reacted with [Ag(SbF6)] in acetone to yield [CpRu((R)-BINOP-F)(acetone)][SbF6] ((R)-7). X-ray structures were obtained for both (R)-6 and (R)-7. The chiral 1-point binding Lewis acid [CpRu((R)-BINOP-F)][SbF6] derived from either (R)-7 or the corresponding aqua complex (R)-8 activates methacrolein and catalyzes the Diels-Alder reaction with cyclopentadiene to give the [4 + 2] cycloadduct with an exo/endo ratio of 99:1 and an ee of 92% of the exo product. Addn. occurs predominantly to the methacrolein Calpha-Re face. In soln., H2O in (R)-8 exchanges readily. Moreover, a 2nd exchange process renders the diastereotopic BINOP-F P atoms equiv. These processes were studied by the application of variable-temp. 1H, 31P, and 17O NMR spectroscopy, variable-pressure 31P and17O NMR spectroscopy, and, using a simpler model complex, d. functional theory (DFT) calcns. The results point to a dissociative mechanism of the aqua ligand and a pendular motion of the BINOP-F ligand. NMR expts. show an energy barrier of 50.7 kJ mol-1 (12.2 kcal mol-1) for the inversion of the pseudo-chirality at the Ru center. [on SciFinder (R)]

The syn/anti conformational equilibrium of o-substituted benzaldehyde chromium tricarbonyl complexes was studied by CD and 1H NMR (NOE). The preferred conformation of the o-methyl-, o-methoxy-, and o-iodobenzaldehyde complexes is anti, while those of the o-trimethyltin and o-trimethylsilyl benzaldehyde complexes is syn. The optical rotation values of (o-trimethylsilyl benzaldehyde)Cr(CO)3 ((1S)-2d) vary from -174 (in ethanol) to +108 (in chloroform).

Two bulky, chiral, monodentate N-heterocyclic carbene ligands were applied to palladium-catalyzed asymmetric C-H arylation to incorporate C(sp(3))-H bond activation. Racemic mixtures of the carbamate starting materials underwent regiodivergent reactions to afford different trans-2,3-substituted indolines. Although this CAr-Calkyl coupling requires high temperatures (140-160 °C), chiral induction is high. This regiodivergent reaction, when carried out with enantiopure starting materials, can lead to single structurally different enantiopure products, depending on the catalyst chirality. The C-H activation at a tertiary center was realized only in the case of a cyclopropyl group. No C-H activation takes place alpha to a tertiary center. A detailed DFT study is included and analyses of methyl versus methylene versus methine C-H activation is used to rationalize experimentally observed regio- and enantioselectivities.

The CuCl2-mediated protocol was extended to the synthesis of 3,3-disubstituted aza-oxindoles. Compounds containing the aza-oxindole structural motif exhibit biological activities such as oral anti-inflammatory activity, and potent TrkA kinase and JAK 3 kinase inhibition. This article discusses the synthesis of 1,3-dimethyl-3-(p-tolyl)-1H-pyrrolo[3, 2-c]pyridine-2,(3H)-one by Cu(II)-mediated direct oxidative coupling. Keywords: N-Methyl-N-(pyridin-4-yl)-2-(p-tolyl)propanamide, 1,3-Dimethyl-3-(p-tolyl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one, CH coupling reaction, CuCl2 mediated aza-oxindole synthesis

The indenyl roof over the chiral Lewis acid catalyst site of [(indenyl)Ru((S,S)-biphop-F)]+ (see picture) gives rise not only to high enantioselectivities in Diels-Alder reactions between enals and cyclopentadiene but also affects the endo/exo diastereoselectivity. The exo product is formed preferentially even with acrolein.

The new chiral bidentate (phosphinoaryl)benzoxazine ligands 2 were applied in asymmetric catalysis. Rhodium and copper complexes catalyzed the hydrosilylation of acetophenone and [4+2] cycloadditions with moderate enantioselectivity. Iridium complexes were used to hyrogenate di-, tri-, and tetrasubstituted alkenes, giving products with moderate to high enantiomer excesses. Enantioselective allylic substitution and Heck reactions catalyzed by [(phosphinoaryl)benzoxazine]palladium complexes occurred with high enantioselectivities. The results were similar to those obtained with the corresponding dihydro(phosphinoaryl)oxazole ligands. Comparison of the structures of (diphenylallyl)(benzoxazine)palladium and (diphenylallyl)(dihydrooxazole)palladium complexes showed that the coordination geometries and the chiral environments of the metal centers are very similar, which explains why the enantioselectivities induced by the two ligand classes are in the same range.

Chiral iron and ruthenium Lewis acids: analogies and differences between the catalysts and the role of the anion in catalytic Diels-Alder reaction. In short: Fe catalysts are faster but Ru analogues are more stable and can be recovered quantitatively. Rational ligand design is shown to result in a large increase in chiral induction.

Sequential addition of a C-nucleophile and a C-electrophile to enantiomerically pure arene tricarbonyl chromium complexes 3a,b, 6, and 8b, containing aryl bound chiral oxazoline, SAMP-hydrazone and chiral imine auxiliaries affording substituted cyclohexadienes. C-Nucleophiles included alkyl-, vinyl-, and phenyl-lithium reagents. C-Electrophiles included methyl iodide, allyl bromide, benzyl bromide, and propargyl bromides. The 1,3-cylohexadienes were obtained with a 1,5,6-substitution pattern. The results are consistent with a diastereoselective exo-nucleophilic addition to an ortho position of the complexed arene, followed by addition of the electrophile to the metal center. With allyl, ben-zyl, and propargyl groups, direct reductive elimination then yielded trans-5,6-substituted products. With methyl iodide, reductive elimination was preceded by CO insertion and acetyl cyclohexadienes were formed exclusively whose in situ deprotonation/alkylation gave products in which three C-substituents had been added across an arene double bond with complete regio- and stereocontrol. The two path-ways reflect migratory aptitude to carbonylation. An X-ray structure determination of the phenyl oxazoline complex 3a allowed a rationalization of observed diastereoselectivity. Asymmetric induction was very high with the oxazoline and the SAMP-hydrazone complexes (>90% de) whereas the chiral benzaldehyde imine complex 8b afforded the substituted diene aldehydes in moderate enantiomeric purity (34-58% ee). Changing the reaction medium from THF to toluene in reactions with 8b resulted in products of the opposite chirality.

Enantioselective lithiation/electrophile addition reactions with eight chiral Li-amide bases, 1 - 8, and five [Cr(arene)(CO)3] complexes, 9 - 13, were investigated. Restriction of conformational freedom in the chiral Li-amide base Li-1, in general, did not result in an increase in asymmetric induction. A new route to enantiomerically enriched (75 - 92%) planar chiral ortho-substituted benzaldehyde complexes via enantioselective lithiation of benzaldimine complexes 16 and 17 is reported. Within the (1S)-enantiomer series of o-substituted benzaldehyde complexes 18a - d, the sign of the specific rotation, [a], is found to be positive, except for the trimethylstannyl derivative 18b. This is interpreted in terms of a reversed conformation of the aldehyde group.

Starting from (R)-1-(2-methoxyphenyl)ethylamine, the title compounds were synthesized. Key steps are a diastereoselective imine alkylation and a Pd-catalyzed biaryl coupling. The benzylic stereogenic centers of the (5R,7R)-azepine induce a strong bias for the atropisomeric conformer having aS axial chirality and pseudo equatorial Me groups.

Two new chiral bidentate (phosphinophenyl)benzoxazine P,N-ligands 2a and 2b were synthesized from highly enantiomer-enriched 2-(1-aminoalkyl)phenols 4. Ligand rac-2a was obtained on refluxing the t-Bu-substituted (aminomethyl)phenol 4a with 2-(diphenylphosphino)benzonitrile in chlorobenzene in the presence of anhydrous ZnCl2 followed by decomplexation (Scheme 2). This reaction, when carried out with (+)-(S)-4a, was accompanied by racemization at the stereogenic center of the alkyl side chain. The enantiomerically pure ligands (+)-(R)-2a and (-)-(S)-2a were obtained using a stepwise procedure via the amides (-)-(R)- and (+)-(S)-5b, respectively, followed by cyclization to benzoxazines (+)-(R)- and (-)-(S)-7b, respectively, with triflic anhydride and by F-atom substitution by diphenylphosphide (Schemes 3 and 5). In the case of the i-Pr analogue 2b, this last step resulted in racemization (Scheme 6). This was overcome by preparing the bromo derivative and introducing the diphenylphosphine group via Br/Li exchange and reaction with chlorodiphenylphosphine (Scheme 7). The first application of (+)-(R)-2a in an asymmetric Heck reaction showed high enantioselectivity (91%) (Scheme 8).

Ease of generation, stablity in solution at ambient temperature, high enantioselectivity in Diels-Alder reactions, efficient catalyst recovery, and large rate differences on variation of the anion are all characteristics of the new Ru Lewis acid [CpRu((S,S)-biphop-F)]+ (biphop-F=(C6F5)2POCH2(Ph)CH2(Ph)OP(C6F5)2). The structure of complex 1 (L=methacrolein, Y=SbF6) provides evidence for a cooperative binding of the dienophile by both the Lewis acid and the anion.

Sequential reaction of the tricarbonyl[(?6-phenyl) carbamate]chromium complex 3 with chiral amide bases (see 4 and 5) and electrophiles yielded planar chiral ortho-substituted complexes 6 with up to 70% enantiomeric excess (ee) (Scheme 2, Table 1 and 2). The enantiomer purity could be increased to >90% ee by fractional crystallization. In all but one case the racemate crystallized selectively, leaving the enantiomerically enriched complex in solution. X-Ray crystal-structure analyses of rac-6a and (1R)-6a suggest that this can be ascribed to a more favorable packing of enantiomers of opposite configuration in the solid state than that of the enantiomerically pure solid. Increasing the temperature of the intermediate ortho-lithiated aryl carbamate complex induced an anionic ortho-Fries rearrangement: The 1,3-transposition of the carbamoyl group yielded the ortho-substituted (?6-benzamide)tricarbonylchromium complexes 10 in 65% yield, after exposure to the electrophile (Scheme 6), and the use of a chiral amide base 5 in the deprotonation step afforded the product with an ee of 54%.