Palladium‐Catalyzed Enantioselective CH Arylation for the Synthesis of P‐Stereogenic Compounds

A palladium‐catalyzed enantioselective C? H arylation of N‐(o‐bromoaryl)‐diarylphosphinic amides is described for the synthesis of phosphorus compounds bearing a P‐stereogenic center. The method provides good enantioselectivities and high yields. The products were readily transformed into P‐chiral biphenyl monophosphine ligands.     

Facts are the Enemy of Truth—Reflections on Serendipitous Discovery and Unforeseen Developments in Asymmetric Catalysis

As Louis Pasteur said, “Chance favors only a prepared mind.” Serendipitous events reorienting the pathway of science often occur through the actions of dedicated individuals with unique cultural and educational backgrounds, an original sense of values, and firm principles. Science is the fountainhead of human knowledge and possesses an indispensable cultural value. Science‐based technologies and the innovations derived from them are the foundation of the civilized society in which we live today. All scientific endeavors begin with observations, or facts. However, the real goal of research activity is to convert accumulated knowledge to something with new technological, economic, or social value. Innovation is an essential aspect to assure the continued survival of humanity. And often, as my half‐century of research reflects, the act of turning facts into values is facilitated by dialogue. Thus, to acquire the necessary combined wisdom, scientists must have ongoing conversations with the societies they serve, as well as with their counterparts in other nations.     

Synthesis and Reactivity of Organometallic Intermediates Relevant to Cobalt‐Catalyzed Hydroformylation

Intermediates relevant to cobalt‐catalyzed alkene hydroformylation have been isolated and evaluated in fundamental organometallic transformations relevant to aldehyde formation. The 18‐electron (R,R)‐(^iPrDuPhos)Co(CO)₂H has been structurally characterized, and it promotes exclusive hydrogenation of styrene in the presence of 50 bar of H₂/CO gas (1:1) at 100 °C. Deuterium‐labeling studies established reversible 2,1‐insertion of styrene into the Co?D bond of (R,R)‐(^iPrDuPhos)Co(CO)₂D. Whereas rapid β‐hydrogen elimination from cobalt alkyls occurred under an N₂ atmosphere, alkylation of (R,R)‐(^iPrDuPhos)Co(CO)₂Cl in the presence of CO enabled the interception of (R,R)‐(^iPrDuPhos)Co(CO)₂C(O)CH₂CH₂Ph, which upon hydrogenolysis under 4 atm H₂ produced the corresponding aldehyde and cobalt hydride, demonstrating the feasibility of elementary steps in hydroformylation. Both the hydride and chloride derivatives, (X=H^?, Cl^?), underwent exchange with free ¹³CO. Under reduced pressure, (R,R)‐(^iPrDuPhos)Co(CO)₂Cl underwent CO dissociation to form (R,R)‐(^iPrDuPhos)Co(CO)Cl.     

Diastereoselective Synthesis of P‐Chirogenic and Atropisomeric 2,2′‐Bisphosphino‐1,1′‐binaphthyls Enabled by Internal Phosphine Oxide Directing Groups

Diphosphine ligands that merge both axial and P‐centered chirality may exhibit superior or unique properties. Herein we report the diastereoselective introduction of P‐centered chirality at the 2‐position of the axially chiral 2′‐(phosphine oxide)‐1,1′‐binaphthyl scaffold. A lithium–bromide exchange reaction of a 2‐bromo‐2′‐(phosphine oxide)‐1,1′‐binaphthyl and treatment with dichlorophosphines followed by a nucleophilic organometallic reagent afforded unsymmetrical 2‐phosphino‐2′‐(phosphine oxide)‐1,1′‐binaphthyls with binaphthyl axial chirality and one or two phosphorus stereocenters with a variety of P substituents. The final diastereomerically pure 2,2′‐bisphosphino‐1,1′‐binaphthyls were obtained by reduction of the phosphine oxide directing group. Preliminary results demonstrated that a ligand with this hybrid chirality could induce higher stereoselectivity in the metal‐complex‐catalyzed asymmetric hydrogenation of a dialkyl ketone.     

Highly Enantioselective Nickel‐Catalyzed Intramolecular Reductive Cyclization of Alkynones

The first asymmetric nickel‐catalyzed intramolecular reductive cyclization of alkynones is reported. A P‐chiral monophosphine and triethylsilane were used as the ligand and the reducing reagent, respectively, to form a series of tertiary allylic alcohols bearing furan/pyran rings in excellent yields and enantioselectivities. This reaction has a broad substrate scope and enabled the efficient synthesis of dehydroxycubebin and chiral dibenzocyclooctadiene skeletons.     

P−P Condensation and P−N/P−P Bond Metathesis: Facile Synthesis of Cationic Tri‐ and Tetraphosphanes

[L_C^RP((PhP)₂C₂H₄)][OTf] ( 4 a,b [OTf]) and [L_C^iPrP(PPh₂)₂][OTf] ( 5 b [OTf]) were prepared from the reaction of imidazoliumyl‐substituted dipyrazolylphosphane triflate salts [L_C^RP(pyr)₂][OTf] ( 3 a,b [OTf]; a : R=Me, b =iPr; L_C^R=1,3‐dialkyl‐4,5‐dimethylimidazol‐2‐yl; pyr=3,5‐dimethylpyrazol‐1‐yl) with the secondary phosphanes PhP(H)C₂H₄P(H)Ph) and Ph₂PH. A stepwise double P?N/P?P bond metathesis to catena‐tetraphosphane‐2,3‐diium triflate salt [(Ph₂P)₂(L_C^MeP)₂][OTf]₂ ( 7 a [OTf]₂) is observed when reacting 3 a [OTf] with diphosphane P₂Ph₄. The coordination ability of 5 b [OTf] was probed with selected coinage metal salts [Cu(CH₃CN)₄]OTf, AgOTf and AuCl(tht) (tht=tetrahydrothiophene). For AuCl(tht), the helical complex [{(Ph₂PPL_C^iPr)Au}₄][OTf]₄ ( 9 [OTf]₄) was unexpectedly formed as a result of a chloride‐induced P?P bond cleavage. The weakly coordinating triflate anion enables the formation of the expected copper(I) and silver(I) complexes [( 5 b )M(CH₃CN)₃][OTf]₂ (M=Cu, Ag) ( 10 [OTf]₂, 11 [OTf]₂).     

Efficient Asymmetric Synthesis of Structurally Diverse P‐Stereogenic Phosphinamides for Catalyst Design

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P‐stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2‐benzoxazaphosphinine‐2‐oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P‐stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.     

A Planar‐Chiral Rhodium(III) Catalyst with a Sterically Demanding Cyclopentadienyl Ligand and Its Application in the Enantioselective Synthesis of Dihydroisoquinolones

The rapid development of enantioselective C?H activation reactions has created a demand for new types of catalysts. Herein, we report the synthesis of a novel planar‐chiral rhodium catalyst [(C₅H₂^tBu₂CH₂^tBu)RhI₂]₂ in two steps from commercially available [(cod)RhCl]₂ and tert‐butylacetylene. Pure enantiomers of the catalyst were obtained through separation of its diastereomeric adducts with natural (S)‐proline. The catalyst promoted enantioselective reactions of aryl hydroxamic acids with strained alkenes to give dihydroisoquinolones in high yields (up to 97 %) and with good stereoselectivity (up to 95 % ee).     

ZnCl2‐Promoted Asymmetric Hydrogenation of β‐Secondary‐Amino Ketones Catalyzed by a P‐Chiral Rh–Bisphosphine Complex

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.     

Rhodium‐Catalyzed Asymmetric Synthesis of Silicon‐Stereogenic Dibenzosiloles by Enantioselective [2+2+2] Cycloaddition

A rhodium‐catalyzed asymmetric synthesis of silicon‐stereogenic dibenzosiloles has been developed through a [2+2+2] cycloaddition of silicon‐containing prochiral triynes with internal alkynes. High yields and enantioselectivities have been achieved by employing an axially chiral monophosphine ligand, and the present catalysis is also applicable to the asymmetric synthesis of a germanium‐stereogenic dibenzogermole. Preliminary studies on the optical properties of these compounds are also described.