Search

A new series of C-1-symmetric P-chirogenic bisphosphine ligands of the type (R)-5,8-Si-Quinox-tBu(3)(Silyl = SiMe3, SiEt3, SiMe2Ph) have been developed. The bulky silyl modulators attached to the ligand backbone fix the phosphine substituents to form rigid chiral environments that can be used for substrate recognition. The ligand showed high performances for a copper(I)-catalyzed asymmetric borylative cyclopropanation of bulky silyl-substituted allylic electrophiles to afford higher disfavored 1,2-cis-silyl-boryl-cyclopropanes than the other possible isomers, trans-cyclopropane and allylboronate (up to 97% yield; 98% ee; cis/trans = >99:1; cyclopropane/allylboronate = >99:1 Detailed computational studies suggested that the highly rigid phosphine conformation, which is virtually undisturbed by the steric interactions with the bulky silyl-substituted allyl electrophiles, is key to the high stereo- and product-selectivities. Furthermore, the detailed computational analysis provided insight into the mechanism of the stereoretention or -inversion of the chiral alkylcopper(I) intermediate in the intramolecular cyclization.

Metal-catalyzed asymmetric synthesis is one of the most important methods for the economical and environmentally benign production of useful optically active compounds. The success of the asymmetric transformations is significantly dependent on the structure and electronic properties of the chiral ligands coordinating to the center metals, and hence the development of highly efficient ligands, especially chiral phosphine ligands, has long been an important research subject in this field. This review article describes the synthesis and applications of P-chiral phosphine ligands possessing chiral centers at the phosphorus atoms. Rationally designed P-chiral phosphine ligands are synthesized by the use of phosphine-boranes as the intermediates. Conformationally rigid and electron-rich P-chiral phosphine ligands exhibit excellent enantioselectivity and high catalytic activity in various transition-metal-catalyzed asymmetric reactions. Recent mechanistic studies of rhodium-catalyzed asymmetric hydrogenation are also described.

A new C2-symmetrical P-chirogenic bisphosphine ligand with silyl substituents on the ligand backbone, (R,R)-5,8-TMS-QuinoxP*, has been developed. This ligand showed higher reactivity and enantioselectivity for the direct enantioconvergent borylation of cyclic allyl electrophiles than its parent ligand, (R,R)-QuinoxP* (e.g., for a piperidine-type substrate: 95% ee vs 76% ee). The borylative kinetic resolution of linear allyl electrophiles was also achieved using (R,R)-5,8-TMS-QuinoxP* (up to 90% ee, s = 46.4). An investigation into the role of the silyl groups on the ligand backbone using X-ray crystallography and computational studies displayed interlocking structures between the phosphine and silyl moieties of (R,R)-5,8-TMS-QuinoxP*. The results of DFT calculations revealed that the entropy effect thermodynamically destabilizes the dormant dimer species in the catalytic cycle to improve the reactivity. Furthermore, in the direct enantioconvergent case, detailed calculations indicated a pronounced enantioselective recognition of carbon-carbon double bonds, which is virtually unaffected by the chirality at the allylic position, as a key for the borylation from both enantiomers of racemic allyl electrophiles.

The first copper(I)-catalyzed enantioselective borylation of racemic benzyl chlorides has been realized by a quadrant-by-quadrant structure modulation of QuinoxP*-type bisphosphine ligands. This reaction converts racemic mixtures of secondary benzyl chlorides into the corresponding chiral benzylboronates with high enantioselectivity (up to 92 % ee). The results of mechanistic studies suggest the formation of a benzylic radical intermediate. The results of DFT calculations indicate that the optimal bisphosphine-copper(I) catalyst engages in noncovalent interactions that efficiently recognize the radical intermediate, and leads to high levels of enantioselectivity.

Here, we report the first synthesis of quasi-stable trimer models of full-length Aβ40 with a toxic conformation using a 1,3,5-phenyltris-l-alanyl linker at position 34, 36, or 38. The only trimer to exhibit weak neurotoxicity against SH-SY5Y cells was the one which was linked at position 38. This suggests that such a propeller-type trimer model is not prone to forming oligomers with potent neurotoxicity, which is in contrast with its corresponding dimer model.

A new

A copper(I)-catalyzed asymmetric borylative cyclopropanation of bulky silyl-substituted allylic electrophiles for 1,2- cis -silyl-boryl-cyclopropanes has been developed. Highly strained cis -cyclopropanes were obtained in excellent yield and stereoselectivity by employing a newly developed backbone-modified three-hindered-quadrant bisphosphine ligand (up to 97% yield; 98% ee; cis / trans = >99:1; cyclopropane/allylboronate = >99:1). Detailed computational studies suggested that the highly rigid phosphine conformation of the backbone-modified ligand, which is virtually undisturbed by the steric interaction with the bulky silyl-substituted allyl electrophiles, is key to the high stereo- and product-selectivity. Furthermore, the detailed computational analysis provided insight into the mechanism of the stereo-retention or -inversion of the chiral alkylcopper(I) intermediate in the intramolecular cyclization.

Asymmetric hydrogenation of sterically hindered substrates still constitutes a long-standing challenge in the area of asymmetric catalysis. Herein, an efficient palladium acetate (an inexpensive Pd salt with low toxicity) catalyzed asymmetric hydrogenation of sterically hindered N-tosylimines is realized with high catalytic activities (S/C up to 5000) and excellent enantioselectivities (ee up to 99.9%). Quantum chemical calculations suggest that uniformly high enantioselectivities are observed due to the structurally different S- and R-reaction pathways., Sterically hindered unsaturated compounds are challenging substrates for asymmetric hydrogenation. Here, the authors report a palladium/chiral (bis)phosphine catalytic system that hydrogenates a number of hindered N-tosylimines with excellent enantioselectivitites.

A bulky three-hindered quadrant bisphosphine ligand, di-1-adamantylphosphino(tert-butylmethylphosphino)methane, named BulkyP*, has been synthesized via a convergent short pathway with chromatograph...

A range of bromothiophenes reacted with lithium boranato(tert-butyl)methylphosphide in the absence of transition-metal catalysts under mild conditions to provide the same 2,5-disubstituted and 2-monosubstituted products regardless of the substitution patterns of the starting bromothiophenes.

Both enantiomers of tert-butylmethylphosphine–borane have been used for the synthesis of P-chiral diphosphines and/or their borane complexes. The enantiopure borane complex of 1,2-bis(tert-butylmethylphosphino)ethane (t-Bu-BisP∗) was prepared in high yield from the secondary phosphine–borane and 1,2-dichloroethane. A mono-chelated Rh-complex of t-Bu-MiniPHOS was prepared and its catalytic activity was examined in the asymmetric hydrogenation of some representative functionalized alkenes. Synthesis of three new P-chiral phosphine ligands with quinoline or quinoxaline backbone is also described together with their enantioinduction ability.

An asymmetric Michael addition of diphenylphosphine to β,γ-unsaturated α-keto esters was developed using a P-stereogenic pincer-Pd complex as a catalyst. The corresponding hydrophosphination products were obtained in good yields (up to 94%) and with moderate to good enantioselectivities (up to 93% ee) under the optimum reaction conditions.

P-Stereogenic PNP type pincer iridium complexes PNPtBuMeIrH2Cl (3) and PNPtBuMeIrH3 (4) were synthesized in reasonable yields and characterized by 1H NMR, 13C NMR, 31P NMR, HRMS and/or single crystal X-ray diffraction. The ORTEP diagram shows that the coordination geometry around the iridium center of complex 3 is approximately octahedral. The chlorinated iridium complex (3) and/or the trihydride iridium complex (4) were used as catalysts in the asymmetric hydrogenation of ketones, olefins and quinoline to provide the desired products with up to 17% enantioselectivity.

Herein, we provide evidence showing that the long-held major–minor concept for catalytic asymmetric reactions needs to be readdressed. The asymmetric hydrogenation of enamide 1 catalyzed by the chiral Rh(I) complex of (R,R)-BenzP* quantitatively yields the corresponding hydrogenated R-product 2 with 89.6% ee. The most abundant catalyst–substrate species in the reaction pool was found to be [Rh((R,R)-BenzP*)(Ph(MeCONH)C═CH2)]+SbF6– (5). This species is also the most reactive to hydrogen among the various Rh complexes. Low-temperature hydrogenation experiments showed direct transformation of 5 to 2 with over 98% ee (R). However, the oxidative addition of H2 to 5 would yield the S-product. Computation has now revealed a low-energy R-enantioselective route, whereby H2 addition to 5 is followed by π-bond dissociation, isomerization of nonchelating Rh species, and recoordination of the double bond before C–H bond formation occurs.

Novel P-stereogenic pincer-Ni complexes {κP,κC,κP-3,5-Me2-2,6-(MetBuPCH2)2C6H}NiCl (3), {κP,κC,κP-3,5-Me2-2,6-(MetBuPCH2)2C6H}NiOTf (4), [{κP,κN,κP-2,6-(MetBuPCH2)2C5H3N}NiCl]Cl (7), [{κP,κN,κP-2,6-(MetBuPCH2)2C5H3N}NiCl]BF4 (8), and [{κP,κN,κP-2,6-(MetBuPCH2)2C5H3N}Ni(NCMe)](BF4)2 (9) were synthesized in 55–84% yields and characterized by 1H NMR, 13C{1H} NMR, 31P{1H} NMR, 19F{1H} NMR, and/or single-crystal X-ray diffractions. The ORTEP diagrams of complexes 3, 7, 8, and 9 show that the coordination geometries around the Ni center in all these structures are approximately square planar but have different bond lengths and angles. These complexes were shown to be active catalysts for the asymmetric aza-Michael addition of α,β-unsaturated nitriles. For most examples good to excellent yields (up to 99%) and moderate enantiomeric excesses (up to 46% ee) were obtained. Notably, the PCP complex 3 exhibited higher catalytic activity in the aza-Michael addition than the PNP complexes 7, 8, and 9. Two achiral PCP-t...

A new P-stereogenic PNP pincer-Pd complex was readily prepared from optically pure 2,6-bis[(boranato(tert-butyl)methylphosphino)methyl]pyridine. It was used in the asymmetric intramolecular hydroamination of amino-1,3-dienes, with the desired products being obtained in good yields and with excellent regioselectivities and up to moderate enantioselectivities. The absolute configuration of one of the hydroamination products was determined by X-ray crystallography studies. This simple and efficient procedure can be used for the synthesis of allyl-type chiral pyrrolidine derivatives.

A new catalytic system has been developed for the asymmetric hydrogenation of β-secondary-amino ketones using a highly efficient P-chiral bisphosphine-rhodium complex in combination with ZnCl2 as the activator of the catalyst. The chiral γ-secondary-amino alcohols were obtained in 90-94 % yields, 90-99 % enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C=substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl2 on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine, in high yields and with excellent enantioselectivities.

Elements of the lanthanide series possess unique electronic and stereochemical properties due to their f-orbitals,and have great potential as reagents and catalysts in organic synthesis.1–4. During the 1970s and 1980s many synthetic reactions and procedures using lanthanide elements were reported, in conjunction with significant development in the chemistry of organolanthanides. Several review articles covering this field of chemistry have appeared.5–11

A Pd-catalyzed asymmetric allylic substitution with 1,3-dithianes as acyl anion equivalents has been developed in high yields and excellent enantioselectivities. The reaction was performed on a gram scale, and the corresponding alkylated products were conveniently converted into several biologically active products. This work provides an alternative strategy utilizing electrophilic carbonyl compounds as nucleophilic species in a Pd-catalyzed allylic substitution.

The mechanism of asymmetric hydrogenation of five representative β-dehydroamino acids catalyzed by rhodium complexes of (R)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane (trichickenfootphos, TCFP) and (R,R)-1,2-bis(tert-butylmethylphosphino)benzene (BenzP*) was studied through a combination of extensive NMR experiments and state-of-the-art DFT computations in order to reveal the crucial factors governing the sense and order of enantioselectivity in this industrially important reaction. The binding mode of the substrate with a Rh(I) catalyst was found to be highly dependent on the nature of the rhodium complex and the substrate. Thus, no substrate binding was detected for [Rh((R,R)-BenzP*)S2]+SbF6– (5) and (E)-3-acetylamino-2-butenoate (2a) even at 173 K. [Rh((R)-TCFP) S2]+BF4– (3) exhibited weak reversible binding with 2a in the temperature interval 173–253 K with the formation of complex 4a, whereas at ambient temperature, slow isomerization of 2a to (Z)-3-acetylamino-2-butenoate (2b) took p...

Novel P-stereogenic PCP pincer-Pd complexes were designed and prepared in short steps from optically pure tert-butylmethylphosphine-borane. These optically active Pd-complexes were successfully applied in asymmetric addition of diarylphosphines to nitroalkenes with high yields and good enantioselectivity.

In this account, the design, synthesis, and application of P-chirogenic phosphine ligands that have been mainly carried out in our laboratory over the last three decades are described. Various enantiopure P-chirogenic phosphine ligands have been efficiently prepared by using phosphine boranes as intermediates. Conformationally rigid and electron-rich P-chirogenic phosphine ligands possessing C2 symmetry as well as a bulky alkyl group and a small group at the phosphorus atoms exhibit excellent enantioselectivities and catalytic efficiency in a variety of transition-metal-catalyzed asymmetric reactions. Enantiopure 2,3-bis(tert-butylmethylphosphino)quinoxaline (QuinoxP*) is an air-stable crystalline solid that shows superior enantioinduction ability in catalytic asymmetric syntheses. Mechanistic studies of Rh-catalyzed asymmetric hydrogenation using structurally simple P-chirogenic phosphine ligands, such as tBu-BisP*, are briefly described.

An asymmetric Michael addition of diphenylphosphine to β,γ-unsaturated α-keto esters was developed using a P-stereogenic pincer-Pd complex as a catalyst. The corresponding hydrophosphination products were obtained in good yields (up to 94%) and with moderate to good enantioselectivities (up to 93% ee) under the optimum reaction conditions.

Improved methods for the preparation of methylene-bridged diphosphine ligands are described. Both enantiomers of the key intermediate tert -butylmethylphosphine–borane were prepared via resolution or by the conversion of one enantiomer into the opposite enantiomer. The precursor borane complexes of bis( tert -butylmethylphosphino)methane ( t -Bu-MiniPHOS), bis((1,1,3,3-tetramethylbutyl)methylphosphino)methane ( t -Oct-MiniPHOS), and ( tert -butylmethylphosphino)(di- tert -butylphosphino)methane (trichickenfootphos) were prepared in good yields and enantiopure form.

The demand for functionalized aromatic compounds is growing rapidly in many research fields. Therefore, the efficient synthesis of desired aromatic compounds is a critical issue in organic synthesis. In this account, we describe new synthetic approaches to versatile aromatic compounds, such as phenols, benzenes, 3-hydroxypyridines, and styrenes, by ring-closing olefin metathesis (RCM)/aromatization and ring-closing enyne metathesis (RCEM)/aromatization of acyclic precursors. The advantages in terms of simplicity, flexibility, and avoidance of the formation of regioisomers are proof of the versatility of this method for the synthesis of aromatic compounds.

The treatment of optically P-chiral tetraphosphine, (3S,6R,9R,12S)-6,9-di-tert-butyl-2,2,3,12,13,13-hexamethyl-3,6,9,12-tetraphosphatetradecane (1), with rhodium(I), palladium(II), and ruthenium(II) complex precursors led to the selective formation of mono-, di-, or trinuclear homo- or heterometallic complexes, [Rh(1)]SbF6 (4), [{Rh(nbd)}2(1)](SbF6)2 (3), [{Pd(η3-allyl)}2(1)](SbF6)2 (5), [{RuCl(η5-C5(CH3)5)}2(1)] (6), and [{RuCl2(η6-benzene)}2(PdCl2)(1)] (8). These complexes were characterized by NMR and X-ray crystallographic analysis.

New synthetic routes to substituted 3-hydroxypyridines 6 are presented. Ring-closing olefin metathesis (RCM)/elimination and RCM/oxidation/deprotection of nitrogen-containing dienes 4 are the key processes of the routes. An application of RCM/oxidation/deprotection to the synthesis of 3-aminopyridine 13f is also described.

An approach to aromatic compounds using combinations of ring-closing olefin metathesis (RCM), dehydration, oxidation, and tautomerization is reported. The RCM reaction of 1,7-diene-3,5-diols, which...

The meta–tele-substitution of 2-(boranatophosphino)fluorobenzenechromium complexes took place with various lithiated secondary phosphine–boranes as nucleophiles to give para-substituted bis(boranatophosphino)benzenechromiums. It was revealed that the yield of the tele-substitution product was strongly affected by the strength of a proton acid. Isotope labeling experiments indicated that 1,5-hydrogen migration was involved in this transformation.

The synthesis of substituted styrenes was achieved by ring-closing enyne metathesis (RCEM)/elimination of enyne substrates 12. The synthetic approach was also effective for a different type of enyne substrate 14, yielding corresponding styrene 15.

The potential of the t-Bu-QuinoxP* ligand (1) as a chiral ligand in asymmetric synthesis was examined. The ligand exhibited good to excellent asymmetric induction in Pd-catalyzed asymmetric allylic substitution of 1,3-diphenyl-2-propenyl acetate (up to 98.7% ee) and in Ru-catalyzed asymmetric hydrogenation of ketones (up to 99.9% ee).

Optically active phosphine ligands possessing stereogenic centers on phosphorus atoms have been synthesized using phosphine-boranes as intermediates. Electron-rich P-chiral phosphine ligands (BisP, MiniPHOS, and DiSquareP) having a bulky alkyl group and a small alkyl group on the phosphorus atom exhibit excellent to almost perfect enantioselectivities in the Rh-catalyzed asymmetric hydrogenation of enamides and related substrates. Air-stable P-chiral phosphine ligands (t-Bu- and 1-Ad-QuinoxP) are also prepared with the phosphine-borane methodology. These ligands have exceedingly high enantioselectivities of up to 99.9% not only in Rh-catalyzed asymmetric hydrogenation but also in Rh- or Pd-catalyzed carbon-carbon bond-forming reactions.

Allyl-type chiral pyrrolidine derivatives are efficiently synthesized by asymmetric intramolecular hydroamination of amino-1,3-dienes with excellent regioselectivities and up to moderate enantioselectivities.

A P-chiral bisphosphine-rhodium complex acts in combination with the catalyst activator zinc chloride as new catalytic system for the asymmetric hydrogenation of β-secondary-amino ketones.

P-Chiral diphosphine ligands, (S,S)-1,2-bis(tert-butylmethylphosphino)ethane [(S,S)-t-Bu-BisP∗], (R,R)-bis(tert-butylmethylphosphino)methane [(R,R)-t-Bu-MiniPHOS], and (R,R)-2,3-bis(tert-butylmethylphosphino)quinoxaline [(R,R)-QuinoxP∗], were applied to the rhodium-catalyzed enantioselective hydrosilylation of simple ketones. The corresponding secondary alcohols were obtained in high yields with good to excellent enantiomeric excesses of up to 99%.

The conformations of the chelate cycles in the X-ray structures of norbornadiene- and cyclooctadiene-rhodium complexes of (R,R)-1,2-bis[(o-methylphenyl)phenylphosphino]ethane are dramatically different. Nevertheless, they demonstrate the same sense of enantioselection in asymmetric hydrogenation of dehydroamino acids.

Dihydroboronium derivatives of (S,S)-1,2-bis(t-butylmethylphosphino)ethane (t-Bu-BisP*) were prepared and used as chiral diphosphine ligand precursors in Rh-catalyzed asymmetric hydrogenation of methyl (Z)-acetamidocinnamate to afford the hydrogenation product in up to 94% enantioselectivity.

Both enantiomers of 1,1′-di-tert-butyl-2,2′-dibenzophosphetenyl were prepared from 2-bromobenzyl chloride and tert-butyldichlorophosphine. These ligands exhibited excellent enantioselectivity in the rhodium catalyzed asymmetric hydrogenation of methyl α-acetylamidocinnamate.

Optically pure (S,S)-1,2-bis[(o-alkylphenyl)phenylphosphino]ethanes 1a–d were prepared in four steps from phenyldichlorophosphine via phosphine-boranes as the intermediates. The rhodium complexes 5a–d of these diphosphines were used for the asymmetric hydrogenations of α-(acylamino)acrylic derivatives including β-disubstituted derivatives. Markedly high enantioselectivity (78–>99%) was observed for the reduction of β-monosubstituted derivatives. β-Disubstituted derivatives were also reduced in considerably high enantioselectivity (up to 90%). The single crystal X-ray analysis of the rhodium complex 5c of (S,S)-1,2-bis[phenyl(5′,6′,7′,8′-tetrahydronaphthyl)phosphino]ethane (1c) revealed its δ-type structure with face orientation of the two tetrahydronaphthyl groups and edge orientation of the two phenyl groups. This conformation corresponds to that of the rhodium complex of 1,2-bis[(o-methoxyphenyl)phenylphosphino]ethane (DIPAMP); the rhodium complex of (R,R)-DIPAMP, whose chirality at phosphorus is opposite that of 5c, exhibits a λ-type structure with the face orientation of the two o-methoxyphenyl groups and the edge orientation of the two phenyl groups. The conformational similarity of these rhodium complexes as well as the stereochemical outcome in the asymmetric hydrogenations means that the coordinative interaction of the methoxy group of DIPAMP with rhodium metal is not the main factor that affects asymmetric induction.