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.     

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.     

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.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Efficient Kinetic Resolution of Sulfur‐Stereogenic Sulfoximines by Exploiting CpXRhIII‐Catalyzed C−H Functionalization

Chiral sulfoximines with stereogenic sulfur atoms are promising motifs in drug discovery. We report an efficient method to access chiral sulfoximines through a C?H functionalization based kinetic resolution. A rhodium(III) complex equipped with a chiral Cp^x ligand selectively participates in conjunction with phthaloyl phenylalanine in the C?H activation of just one of the two sulfoximine enantiomers. The intermediate reacts with various diazo compounds, providing access to chiral 1,2‐benzothiazines with synthetically valuable substitution patterns. Both sulfoximines and 1,2‐benzothiazines were obtained in high yields and excellent enantioselectivity, with s‐values of up to 200. The utility of the method is illustrated by the synthesis of the key intermediates of two pharmacologically relevant kinase inhibitors.     

Asymmetric Hydrogenations (Nobel Lecture)

The start of the development of catalysts for asymmetric hydrogenation was the concept of replacing the triphenylphosphane ligand of the Wilkinson catalyst with a chiral ligand. With the new catalysts, it should be possible to hydrogenate prochiral olefins. Knowles and his co‐workers were convinced that the phosphorus atom played a central role in this selectivity, as only chiral phosphorus ligands such as (R,R)‐DIPAMP, whose stereogenic center lies directly on the phosphorus atom, lead to high enantiomeric excesses when used as catalysts in asymmetric hydrogenation reactions. This hypothesis was disproven by the development of ligands with chiral carbon backbones. Although the exact mechanism of action of the phosphane ligands is not incontrovertibly determined to this day, they provide a simple entry to a large number of chiral compounds.     

Asymmetric P−C Bond Formation: Diastereoselective Synthesis of Adjacent P,C‐Stereogenic Allylic Phosphorus Compounds

A novel catalytic asymmetric P?C bond formation between phosphinates/phosphine oxide and allylic carbonates was developed. This methodology could not only afford a variety of functionalized adjacent P,C‐stereogenic phosphorus compounds in high yields with high regio‐ and diastereoselectivities but also provide an alternative strategy to access enantiomerically enriched (S_P)‐phosphinates through kinetic resolution.     

Synthesis of a Stimuli‐Responsive P‐Chiral Polymer with Chiral Phosphorus Atoms and Azobenzene Moieties in the Main Chain

A reaction of the P‐chiral compound (S,S)‐1,2‐bis(boranato(tert‐butyl)methylphosphino)ethane with an azobenzene derivative gave stimuli‐responsive polymers with P‐chiral phosphines in the main chain. This is the first example of a stimuli‐responsive P‐chiral polymer. The polymer isomerized from the trans to the cis form upon UV irradiation and reverted to the trans form reversibly. The polymer was able to coordinate to platinum, and the resulting polymer complex exhibited the Cotton effect owing to the chirality of the phosphorus atoms. The structure of the P‐chiral polymer obtained could be changed reversibly by light and thermal stimuli, and the polymer chain was induced to rotate helically when complexed with transition metals through the chiral phosphorus atoms.     

A Regio‐ and Stereoselective ω‐Transaminase/Monoamine Oxidase Cascade for the Synthesis of Chiral 2,5‐Disubstituted Pyrrolidines

Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds. Herein, a novel one‐pot ω‐transaminase (TA)/monoamine oxidase (MAO‐N) cascade process for the synthesis of chiral 2,5‐disubstituted pyrrolidines is reported. The reactions proceeded with excellent enantio‐ and diastereoselectivity (>94 % ee; >98 % de) and can be performed on a preparative scale. This methodology exploits the complementary regio‐ and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the transaminase is not affected by the monoamine oxidase, and highlights the potential of this multienzyme cascade for the efficient synthesis of chiral building blocks.     

Catalytic Asymmetric Mannich‐Type Reaction of N‐Alkylidene‐α‐Aminoacetonitrile with Ketimines

Optically active vicinal diamines are versatile chiral building blocks in organic synthesis. A soft Lewis acid/hard Brønsted base cooperative catalyst allows for an efficient stereoselective coupling of N‐alkylidene‐α‐aminoacetonitrile and ketimines to access this class of compounds bearing consecutive tetra‐ and trisubstituted stereogenic centers. The strategic use of a soft Lewis basic thiophosphinoyl group for ketimines is the key to promoting the reaction, and aliphatic ketimines serve as suitable substrates with as little as 3 mol % catalyst loading.     

A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine,and (+)‐1‐epi‐Castanospermine

The asymmetric total synthesis of natural azasugars (+)‐castanospermine, (+)‐7‐deoxy‐6‐epi‐castanospermine, and synthetic (+)‐1‐epi‐castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)‐ 8 . The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama‐type reaction with either chiral or achiral aldehydes (≥95 % de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5‐(α‐hydroxyalkyl)tetramic acids, such as 17/34 , and 5‐(α‐hydroxyalkyl)‐4‐hydroxyl‐2‐pyrrolidinones, such as 18 and 25/35 a . The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.     

5‐Hydroxyalkyl derivatives of tert‐butyl 2‐oxo‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate: diastereoselectivity of the Mukaiyama crossed‐aldol‐type reaction

The title compounds, rac‐(1′R,2R)‐tert‐butyl 2‐(1′‐hydroxyethyl)‐3‐(2‐nitrophenyl)‐5‐oxo‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate, C₁₇H₂₀N₂O₆, (I), rac‐(1′S,2R)‐tert‐butyl 2‐[1′‐hydroxy‐3′‐(methoxycarbonyl)propyl]‐3‐(2‐nitrophenyl)‐5‐oxo‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate, C₂₀H₂₄N₂O₈, (II), and rac‐(1′S,2R)‐tert‐butyl 2‐(4′‐bromo‐1′‐hydroxybutyl)‐5‐oxo‐2,5‐dihydro‐1H‐pyrrole‐1‐carboxylate, C₁₃H₂₀BrNO₄, (III), are 5‐hydroxyalkyl derivatives of tert‐butyl 2‐oxo‐2,5‐dihydropyrrole‐1‐carboxylate. In all three compounds, the tert‐butoxycarbonyl (Boc) unit is orientated in the same manner with respect to the mean plane through the 2‐oxo‐2,5‐dihydro‐1H‐pyrrole ring. The hydroxyl substituent at one of the newly created chiral centres, which have relative R,R stereochemistry, is trans with respect to the oxo group of the pyrrole ring in (I), synthesized using acetaldehyde. When a larger aldehyde was used, as in compounds (II) and (III), the hydroxyl substituent was found to be cis with respect to the oxo group of the pyrrole ring. Here, the relative stereochemistry of the newly created chiral centres is R,S. In compound (I), O—H...O hydrogen bonding leads to an interesting hexagonal arrangement of symmetry‐related molecules. In (II) and (III), the hydroxyl groups are involved in bifurcated O—H...O hydrogen bonds, and centrosymmetric hydrogen‐bonded dimers are formed. The Mukaiyama crossed‐aldol‐type reaction was successful when using the 2‐nitrophenyl‐substituted hydroxypyrrole, or the unsubstituted hydroxypyrrole, and boron trifluoride diethyl ether as catalyst. The synthetic procedure leads to a syn configuration of the two newly created chiral centres in all three compounds.     

Stereoselective P5‐Deltacyclene Alkylation,an Efficient Route to New Asymmetric P‐C‐Cage Compounds

Tetra‐tert‐butyl‐P₅‐deltacyclene 5 represents one of only two asymmetric P‐C cage compounds, which are available in highly enantiomerically enriched versions. This paper reports about stereoselective substitution reactions of 5 to develop the chemistry of optically active P‐C cages further. Electrophilic substitution of the only secondary phosphorus atom P1 of the cage with methyl and benzyl groups was achieved with 92 % and >99 % de, but the yields of the reactions are limited due to competing processes. The uncatalyzed hydrophosphination reaction of a monosubstituted allene and two α,β‐unsaturated carbonyl compounds with 5 proved to be the method of choice. cis‐Butanone‐P₅‐deltacyclene 12 is formed in 92 % yield and with >99 % de and cis‐pentanone‐P₅‐deltacyclene 13a is accessible with >99 % de for P1 and 92 % de for the attached carbon atom at the same time. Besides stereoselectivity, the hydrophosphination reaction of 5 performs with a good regioselectivity. The chiral cage 5 controls the stereoselectivity of its reactions for the cage elements as well as for the α position of a substituent.     

Pd(II)‐Catalyzed Tandem Enantioselective Methylene C(sp3)−H Alkenylation–Aza‐Wacker Cyclization to Access β‐Stereogenic γ‐Lactams

Herein, we describe an unprecedented cascade reaction to β‐stereogenic γ‐lactams involving Pd(II)‐catalyzed enantioselective aliphatic methylene C(sp³)?H alkenylation–aza‐Wacker cyclization through syn‐aminopalladation. Readily available 3,3′‐substituted BINOLs are used as chiral ligands, providing the corresponding γ‐lactams with broad scope and high enantioselectivities (up to 98 % ee).     

(3aS,7aS)‐1‐{2‐Oxo‐1,3‐bis­[(S)‐1‐phen­ylethyl]­per­hydro‐1,3,2λ5‐benzodi­aza­phosphol‐2‐yl}‐1‐phenylmethanol: a mixture of dia­stereoiso­mers in a disordered crystal

In the title compound, C₂₉H₃₅N₂O₂P, the stereogenic C center α to the P atom, formed during the Pudovik condensation reaction between a deprotonated chiral diaza­phosphole and benz­aldehyde, has disordered substituents, giving a mixture of Cα‐R and Cα‐S diastereoisomers. Moreover, this compound crystallizes with two independent mol­ecules in the asymmetric unit. The observed configuration at the Cα atom is 0.741 (6)‐S mixed with 0.259 (6)‐R, indicating diastereoisomeric enrichment during crystallization. Data from solution and solid‐state studies consistently point to an epimerization process at the Cα atom.     

Palladium‐Catalyzed Asymmetric Synthesis of Silicon‐Stereogenic 5,10‐Dihydrophenazasilines via Enantioselective 1,5‐Palladium Migration

A palladium‐catalyzed asymmetric synthesis of silicon‐stereogenic 5,10‐dihydrophenazasilines was developed that proceeds via an unprecedented enantioselective 1,5‐palladium migration. High enantioselectivity was achieved by employing 4,4′‐bis(trimethylsilyl) (R )‐Binap as the chiral ligand, and a series of mechanistic investigations were carried out to probe the catalytic cycle of this process.     

Enantiopure Narrow Bite‐Angle POP Ligands: Synthesis and Catalytic Performance in Asymmetric Hydroformylations and Hydrogenations

Herein is reported the preparation of a set of narrow bite‐angle P–OP ligands the backbone of which contains a stereogenic carbon atom. The synthesis was based on a Corey–Bakshi–Shibata (CBS)‐catalyzed asymmetric reduction of phosphomides. The structure of the resulting 1,1‐P–OP ligands, which was selectively tuned through adequate combination of the configuration of the stereogenic carbon atom, its substituent, and the phosphite fragment, proved crucial for providing a rigid environment around the metal center, as evidenced by X‐ray crystallography. These new ligands enabled very good catalytic properties in the Rh‐mediated enantioselective hydrogenation and hydroformylation of challenging and model substrates (up to 99 % ee). Whereas for asymmetric hydrogenation the optimal P–OP ligand depended on the substrate, for hydroformylation, a single ligand was the highest‐performing one for almost all studied substrates: it contains an R‐configured stereogenic carbon atom between the two phosphorus ligating groups, and an S‐configured 3,3′‐diphenyl‐substituted biaryl unit.     

Enantioselective Formal [3+2] Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3‐Oxazolidines with Quaternary Stereogenic Center

The formal [3+2] cycloaddition of epoxides and unsaturated compounds is a powerful methodology for the synthesis of densely functionalized five‐membered heterocyclic compounds containing oxygen. Described is a novel enantioselective formal [3+2] cycloaddition of epoxides under Brønsted base catalysis. The bis(guanidino)iminophosphorane as a chiral organosuperbase catalyst enabled the enantioselective reaction of β,γ‐epoxysulfones with imines, owing to its strong basicity and high stereocontrolling ability, to provide enantioenriched 1,3‐oxazolidines having two stereogenic centers, including a quaternary one, in a highly diastereo‐ and enantioselective manner.     

Construction of a Chiral Silicon Center by Rhodium‐Catalyzed Enantioselective Intramolecular Hydrosilylation

Rhodium‐catalyzed enantioselective desymmetrizing intramolecular hydrosilylation of symmetrically disubstituted hydrosilanes is described. The original axially chiral phenanthroline ligand (S)‐BinThro (Binol‐derived phenanthroline) was found to work as an effective chiral catalyst for this transformation. A chiral silicon stereogenic center is one of the chiral motifs gaining much attention in asymmetric syntheses and the present protocol provides cyclic five‐membered organosilanes incorporating chiral silicon centers with high enantioselectivities (up to 91 % ee). The putative active Rh^I catalyst takes the form of an N,N,O‐tridentate coordination complex, as determined by several complementary experiments.     

Two pseudo‐enantiomeric forms of N‐benzyl‐4‐hydroxy‐1‐methyl‐2,2‐dioxo‐1H‐2λ6,1‐benzothiazine‐3‐carboxamide and their analgesic properties

The fact that molecular crystals exist as different polymorphic modifications and the identification of as many polymorphs as possible are important considerations for the pharmaceutic industry. The molecule of N‐benzyl‐4‐hydroxy‐1‐methyl‐2,2‐dioxo‐1H‐2λ⁶,1‐benzothiazine‐3‐carboxamide, C₁₇H₁₆N₂O₄S, does not contain a stereogenic atom, but intramolecular hydrogen‐bonding interactions engender enantiomeric chiral conformations as a labile racemic mixture. The title compound crystallized in a solvent‐dependent single chiral conformation within one of two conformationally polymorphic P2₁2₁2₁ orthorhombic chiral crystals (denoted forms A and B). Each of these pseudo‐enantiomorphic crystals contains one of two pseudo‐enantiomeric diastereomers. Form A was obtained from methylene chloride and form B can be crystallized from N,N‐dimethylformamide, ethanol, ethyl acetate or xylene. Pharmacological studies with solid–particulate suspensions have shown that crystalline form A exhibits an almost fourfold higher antinociceptive activity compared to form B.