Pybox Research Articles

Synthesis of a Novel Unsymmetrical Bisoxazoline Ligand with sp² Bridging Carbon

A novel unsymmetrical bisoxazoline ligand was synthesized in one step by the Knoevenagel condensation of aldehydes with a C 2 -symmetric indane-derived bisoxazoline having two acidic hydrogens connected to the bridging carbon. The electronic properties of incorporated bridge substituent due to π-π conjugation with oxazoline rings can affect the catalytic performance of the ligand in asymmetric syntheses, as was shown for the Henry reaction between benzaldehyde and nitromethane.

“Catalysis in a Tea Bag”: Synthesis, Catalytic Performance and Recycling of Dendrimer‐Immobilised Bis‐ and Trisoxazoline Copper Catalysts

Bis- and trisoxazolines (BOX and trisox), containing a linker unit in the ligand backbone that allows their covalent attachment to carbosilane dendrimers, have been employed as polyfunctional ligands for recyclable Cu(II) Lewis acid catalysts that were immobilised in a membrane bag. The oxazolines contained an alkynyl unit attached to their backbone that was deprotonated with LDA or BuLi and then reacted with the chlorosilyl termini of zeroth-, first- and second-generation carbosilane dendrimers in the presence of TlPF(6). The functionalised dendritic systems were subsequently separated from excess ligand by way of dialysis. The general catalytic potential of these systems was assessed by studying two benchmark reactions, the alpha-hydrazination of a beta-keto ester as well as the Henry reaction of 2-nitrobenzaldehyde with nitromethane. For both reactions the bisoxazoline-based catalysts displayed superior selectivity and, in particular, catalyst activity. The latter was interpreted as being due to the hindered decoordination of the third oxazoline unit, the key step in the generation of the active catalyst, in the immobilised trisox-copper complexes. Solutions of the second-generation dendrimer catalysts were placed in membrane bags, fabricated from commercially available dialysis membranes, with the purpose of catalyst recycling based on dialysis. Overall, the supported BOX catalyst gave good and highly reproducible results throughout the study, whereas the performance of the trisox dendrimer system decreased monotonically. The reason for the different behaviour is the markedly lower activity of trisox-based catalysts relative to those based on the BOX ligand. This necessitated an increased reaction time for each cycle of the trisox derivatives, resulting in higher levels of catalyst leaching, which was attributed to a modification of the structure of the membrane by its exposure to the solvent trifluoroethanol at 40 degrees C.

Design, synthesis and coordination chemistry of sidearm substituted bisoxazoline ligands

We describe herein the design, synthesis and coordination chemistry of a novel ligand motif that combines a bisoxazoline with a third flexible chelating substituent (“tail”). Four such ligands ( 6- 9) were synthesized from phenylglycine in 4–5 steps each in ca. 20% overall yield. Coordination of 6 and 7 to [Re(CO) 4Cl] 2 yielded crystals suitable for X-ray analysis. Likewise, crystals were obtained from coordination of 6 to FeCl 2. The solid state structures of the resulting complexes ( 10– 12) reveal κ 2 binding of the bisoxazoline motif; however, the structures of complexes 10 and 12 show that the “tail” is poised above the metal center, demonstrating the potential for alternate binding modes in solution. The complexes exhibit a relatively planar 6-membered chelate structure, in contrast to the boat conformation typical of trispyrazolylborate complexes.

末端アセチレンの分子内オキシ-カルボニル化反応：不斉触媒化およびタンデム型反応への応用

The intramolecular oxy-carbonylation of terminal acetylenes is considered to be a useful method for the conversion of an acetylene unit to a β-ketoester unit utilizing neighboring group participation. The first examples of an asymmetric version of this reaction have been achieved, using some new chiral bis-oxazoline (box) ligands. To demonstrate the utility of this reaction, the chiral total synthesis of (+)-bakkenolide-A was achieved. The box ligand plays an important role in the intramolecular oxy-carbonylation of propargyl acetate having an extra terminal acetylene. In the absence of the box ligand, the second triple bond did not react, affording a cyclic orthoester. The use of the box ligand changed the course of the reaction significantly, yielding either 4-cyclopentene-1,3-dione or a bicyclic lactone by tandem carbonylative cyclization as a result of the reaction (insertion or methoxy-palladation) of the second triple bond.

Facile synthesis of a chiral urea bridged bisoxazoline ligand and structural characterization of its bis-copper(ii)-chloride complex

A facile synthesis of a new bisoxazoline ligand is described. This ligand contains a urea bridging unit and is capable of stabilizing bimetallic complexes. An X-ray crystal structure of a bis-copper complex is reported.

Synthesis of a new spiro-BOX ligand and its application in enantioselective allylic cyclization based on carbopalladation of allenyl hydrazines

In this paper, we developed a new bisoxazoline ligand with a spiro skeleton and a alpha-naphthylmethyl substituent, i.e. (Ra,S,S)-L3, which has been successfully applied to the highly enantioselective cyclic allylation based on the carbopalladation of 3,4-allenyl hydrazines with ee values ranging from 92-95%.

ChemInform Abstract: Asymmetric Henry Reactions Catalyzed by Metal Complexes of Chiral Boron‐Bridged Bisoxazoline (Borabox) Ligands.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Electrostatically immobilised BOX and PYBOX metal catalysts: application to ene reactions

Copper(I), copper(II) and scandium(III) triflate complexes of BOX and PYBOX ligands have been electrostatically immobilised on silica. The performance of the immobilised catalysts, in the two carbonyl-ene reactions studied, compares very well with that of their homogeneous equivalents. The immobilised catalysts were successfully reused a number of times. In the case of a scandium complex, a variation in enantioselectivity of up to 73% was observed on immobilisation compared to its use homogeneously. The reason for this variation in enantioselectivity is explored with the aid of molecular modelling.

A Gold‐Catalyzed Entry into the Sesquisabinene and Sesquithujene Families of Terpenoids and Formal Total Syntheses of Cedrene and Cedrol

A concise entry into the bicyclic cyclopropyl ketone derivatives 5 and 6 by way of a gold-catalyzed Ohloff-Rautenstrauch-type enyne cycloisomerization is described. The required substrates were prepared by an asymmetric addition of the branched allylzinc reagent 21 to the alkynyl aldehyde 17 mediated by the deprotonated bisoxazoline (BOX) ligand 22. Compounds 5 and 6 were then converted into a host of different members of the sesquisabina- and sesquithuja families of terpenoids, inter alia with the aid of iron-catalyzed cross-coupling reactions. As the relative and absolute configuration of 5 and 6 could be unambiguously established, the synthetic samples allowed the previously unknown stereostructures of various such terpenoids to be unraveled, including cis-sesquisabinene hydrate (33), 7-epi-sesquithujene (36), sesquisabinene B (37) and epoxy-sesquithujene (45). Moreover, the preparation of 6 also constitutes a formal total synthesis of cedrene (11) and cedrol (12).

A Synthesis of Callipeltoside A

This synthesis established the absolute stereochemistry of callipeltoside A, a marine macrolide with cytotoxicity towards human bronchopulmonary non-small-cell lung carcinoma. A very efficient vinylogous aldol reaction catalyzed by BOX ligand K created the stereocenter at C13 and the trisubstituted alkene in H.

Chiral Boron‐Bridged Bisoxazoline (Borabox) Ligands: Structures and Reactivities of Pd and Cu Complexes

Anionic boron-bridged bisoxazolines (borabox ligands) have been synthesized and characterized in their protonated forms. The ligands are tuneable over a wide range, allowing either alkyl or aryl substituents at the oxazoline rings and the central bridging boron atom. The structural parameters of this new ligand type have been investigated by X-ray analyses of palladium and copper complexes. Electronic properties have been studied by (13)C NMR spectroscopy and by DFT calculations on palladium allyl complexes and compared to those of analogous bisoxazoline (box) complexes. Borabox complexes are more electron-rich at the metal center than their neutral box congeners, and as a consequence of the longer bonds between the bridging atom and the oxazoline rings, their bite angles are larger. Palladium(II) complexes bearing an unsubstituted allyl ligand and homoleptic copper(II) complexes each possess an almost flat chelate ring. NMR analysis of a (1,3-diphenylallyl)(borabox)palladium complex showed a 92:8 mixture of (syn,syn) and (anti,syn) allyl isomers, in contrast with a previously reported box analogue that existed exclusively in the (syn,syn) form. Comparison of the corresponding crystal structures revealed that the distance between the bisoxazoline and the allyl ligand in the borabox complex is shorter. In the copper-catalyzed allylic oxidation of cyclohexene and cyclopentene with tert-butyl perbenzoate, borabox ligands gave results similar-and in some cases superior-to those obtained with analogous box ligands.

Development of Catalytic Asymmetric 1,4-Addition and [3 + 2] Cycloaddition Reactions Using Chiral Calcium Complexes

Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities.

Asymmetric Henry Reactions Catalyzed by Metal Complexes of Chiral Boron‐Bridged Bisoxazoline (borabox) Ligands

AbstractMetal complexes of boron‐bridged bisoxazolines (borabox ligands) were evaluated as catalysts for the Henry reaction. Copper(II) complexes induced high enantio‐ and diastereoselectivity in reactions with nitroethane and nitropropane. The amount of base added had a strong influence on the formation of the chiral complex and the enantioselectivity. Comparison with the corresponding dimethylmethylene‐bridged bisoxazoline and other privileged ligands showed that borabox was the most suitable ligand system for the enantio‐ and diastereoselective formation of nitroalcohols derived from nitropropane and aliphatic aldehydes.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Enantiomer‐Selective Carbamoylation of Racemic α‐Hydroxy γ‐Lactones with Chiral CuII Catalysts: An Example of a Highly Active Lewis Acid Catalyzed Reaction

Enantiomer-selective carbamoylation of racemic alpha-hydroxy gamma-lactones with half equivalents of isocyanates in the presence of chiral Cu(II) catalysts was studied. Among a series of catalyst bearing chiral bis(oxazoline) (box) and pyridine(bisoxazoline) ligands, [Cu(tBu-box)]X(2) [X=OSO(2)CF(3) (3 a), SbF(6) (3 b)] showed the highest enantioselectivity in the reaction of pantolactone (1 a). Use of n-C(3)H(7)NCO, a small alkyl isocyanate, in CH(2)Cl(2) solution was important to achieve a high level of enantiomer selection. The tBu-box-Cu(II) catalyst efficiently differentiated two enantiomers of beta-substituted alpha-hydroxy gamma-lactones under the optimized reaction conditions, resulting in a stereoselectivity factor (s=k(fast)/k(slow)) of up to 209. Furthermore, this catalyst is highly active, so that the carbamoylation can be conducted with a substrate-to-catalyst molar ratio of 2000-3000. A catalytic cycle of this reaction is also proposed.

Surface confinement effects in enantioselective catalysis: Design of new heterogeneous chiral catalysts based on C 1-symmetric bisoxazolines and their application in cyclopropanation reactions

Surface confinement effects are extremely important in determining the stereochemical course of cyclopropanation reactions catalyzed by C 2-symmetric bisoxazoline–copper complexes immobilized on laponite. In the case of the PhBox ligand, complete reversal of trans/ cis-diastereoselectivity is observed, as well as a reversal in the absolute configuration of the major cis-cyclopropane. Furthermore, the enantioselectivity obtained with the immobilized catalyst is better than that obtained in the homogeneous phase, indicating that support effects can be beneficial to the stereoselectivity of the reaction. The design of C 1-symmetric bisoxazoline ligands specifically for heterogeneous catalysis allows improvement of the cis-selectivity of the benchmark cyclopropanation reaction up to 91% cis-cyclopropanes. This finding is in agreement with a closer complex surface approach. Experiments carried out with reagents with a greater steric demand highlight the existence of reaction channels in which the ester group points toward the support surface, a factor that was disregarded in the former stereoinduction model.

A General and Efficient Route to 3-O-Modified Carbohydrate Bis(oxazoline) Ligands

An efficient route to derivatives of carbohydrate-based bis(oxazoline) ligands with 3-O substituents of varying steric demand is described. The synthesis of the new ligands proceeds via a thioglucoside key intermediate, the double cyclisation reaction to the desired bis(oxazolines) is initiated with N-iodo succinimide under mild conditions. Employing this strategy, four new 3-O-modified bis(oxazoline) ligands were obtained in good yields.

Surface Confinement Effects on Enantioselective Cyclopropanation. Reactions with Supported Chiral 8-Oxazolinylquinoline−Copper Complexes

Chiral quinolinoxazoline ligands, a class of C1-symmetric chiral ligands, are tested in the enantioselective supported catalysis of a cyclopropanation reaction, trying to improve surface confinement effects of the clay support on the reaction stereoselectivity. In the case of trans/cis diastereoselectivity, these surface effects lead to a complete reversal of selectivity, with cis selectivity values superior to those previously found using C2-symmetryic bisoxazoline ligands. On the other hand, the enantioselectivities do not display important variations in the supported catalysts. A theoretical (DFT) mechanistic study is carried out to explain the origin of the enantioselectivity in homogeneous phase at a molecular level.

Enantioselectivity in the synthesis of 3,5-disubstituted Δ 2-isoxazolines

The R-isomer of ISO-1, a 3,5-disubstituted Δ 2-isoxazoline, has been implicated as a potential therapeutic agent for the treatment of Type 1 Diabetes via the antagonism of macrophage migration inhibitory factor (MIF). Δ 2-Isoxazolines can be prepared by the palladium(II)-mediated cyclization of substituted β,γ-unsaturated oximes. While this reaction results in racemic mixtures, we have developed a stereoselective variant of this method based on the incorporation of an enantiomeric palladium complex in the reaction mixture. The use of chiral bisoxazoline ligands in the palladium(II)-mediated ring closure reaction has been shown to enhance the enantiomeric excess due to chirality at C5 of the Δ 2-isoxazoline.

Parallel kinetic resolution of propargyl ketols: formal synthesis of (+)-bakkenolide A

We describe an intriguing new example of a parallel kinetic resolution; an asymmetric cyclization–carbonylation of propargyl ketols catalyzed by palladium(II) with chiral bisoxazoline (box) ligands. The 2 S,3 S enantiomer of (±)- 6 was preferentially converted to 13 (45–49% yields, 37–46% ee), and the 2 R,3 R enantiomer of (±)- 6 was preferentially converted to 14 (21–23% yields, 92–97% ee). As an application of this reaction, formal synthesis of (+)-bakkenolide A was achieved.

Efficient Synthesis of (3R,3aS,6aR)- Hexahydrofuro[2,3-b]furan-3-ol from Glycolaldehyde

A one-step diastereoselective (up to 98:2) synthesis of the bis-furan alcohol of Darunavir and other HIV drug candidates has been achieved utilizing the novel cyclization of glycolaldehyde and 2,3-dihydrofuran. The cycloaddition was catalyzed by a variety of catalysts including those formed from tin(II) triflate and common chiral ligands such as BINAP and Evans's box ligands. An efficient and unique enzymatic process enhanced the enantiomeric purity to provide the target in optically pure form.