Enantioselective Allylic Oxidation Research Articles

Copper‐Catalyzed Simultaneous Dehydrogenation and Enantioselective Allylic Oxidation of Alkanes Using Chiral Heterogeneous Ligands to Produce Allylic Esters and Theoretical Investigation of the Mechanism

ABSTRACTA new asymmetric method for preparing chiral allylic esters from various unactivated alkanes through simultaneous dehydrogenation and enantioselective allylic oxidation in the presence of chiral heterogeneous oxazoline–based ligands is reported for the first time. For this purpose, chiral amino oxazoline ligands, synthesized from chiral amino alcohols and cyanogen bromide, were immobilized on modified MCM‐41 mesoporous silica. These chiral heterogeneous ligands were then characterized using Fourier‐transform infrared spectroscopy, thermogravimetric analysis, X‐ray diffraction, scanning electron microscopy, energy‐dispersive X‐ray spectroscopy, and Brunauer–Emmett–Teller and Barrett–Joyner–Halenda techniques. Finally, copper complexes of these ligands were employed in the synthesis of chiral allylic esters, achieving the best result with a 90% yield and 77% enantiomeric excess. Evaluation of the recyclability of the chiral heterogeneous catalysts revealed that they can be reused three times without a noticeable reduction in the results. In addition, the mechanism of formation of the chiral allylic esters was investigated using a density functional theory method.

Application of chiral Betti base-copper complexes in enantioselective allylic oxidation of olefins, computational studies of the Betti bases, and docking of the resulting chiral allylic esters

Chiral (R)- and (S)-Betti bases have been initially synthesized from resolution of the corresponding racemic mixture by diastereomeric recrystallization method using l-(+)-tartaric acid, and then the copper complexes of the Betti bases have been studied in enantioselective allylic CH bond oxidation of olefins. This kind of ligands gave enantioenriched allylic esters with good to high yields and satisfactory enantioselectivities under optimized conditions. In addition, the thermodynamic stability of the Betti base mixture and binding energy between the racemic Betti bases and l-(+)-tartaric acid in the resolution process have been calculated using the M06–2X method and 6–311++G(d,p) basis set. Furthermore, the bioactivity of the synthesized chiral allylic esters has been investigated towards the PI3Kα enzyme with the use of AutoDock Vina.

Rediscovering Sulfinylamines as Reagents for Organic Synthesis.

Sulfinylamines (R−N=S=O), monoaza analogues of sulfur dioxide, have been known for well over a century, and their reactivity as sulfur electrophiles and in Diels‐Alder reactions is well‐established. However, they have only rarely been used in organic synthesis in recent decades despite the increasing prominence of compounds containing N=S=O functionality, such as sulfoximines and sulfonimidamides. This Minireview aims to bring wider visibility to the unique chemistry enabled by this class of compounds. We focus on advances from the last 10 years, including the first examples of their use in the one‐pot syntheses of sulfoximines and sulfonimidamides. Also covered are the reactions of sulfinylamines with carbon‐centred radicals, their use for formation of heterocycles through cycloadditions, and catalytic enantioselective allylic oxidation of alkenes via a hetero‐ene reaction. These examples highlight the different reactivity modes of sulfinylamines and their underappreciated potential for forming molecules which contain high‐ or low‐valent sulfur, or even no sulfur at all.

One‐Pot Biocatalytic Double Oxidation of α‐Isophorone for the Synthesis of Ketoisophorone

AbstractThe chemical synthesis of ketoisophorone, a valuable building block of vitamins and pharmaceuticals, suffers from several drawbacks in terms of reaction conditions and selectivity. Herein, the first biocatalytic one‐pot double oxidation of the readily available α‐isophorone to ketoisophorone is described. Variants of the self‐sufficient P450cam‐RhFRed with improved activity have been identified to perform the first step of the designed cascade (regio‐ and enantioselective allylic oxidation of α‐isophorone to 4‐hydroxy‐α‐isophorone). For the second step, the screening of a broad panel of alcohol dehydrogenases (ADHs) led to the identification of Cm‐ADH10 from Candida magnoliae. The crystal structure of Cm‐ADH10 was solved and docking experiments confirmed the preferred position and geometry of the substrate for catalysis. The synthesis of ketoisophorone was demonstrated both as a one‐pot two‐step process and as a cascade process employing designer cells co‐expressing the two biocatalysts, with a productivity of up to 1.4 g L−1 d−1.

Synthesis of Enantiomerically Pure (8S,9S,10R,6Z)-Trihydroxyoctadec-6-enoic Acid.

We have accomplished the asymmetric synthesis of (8S,9S,10R,6Z)-trihydroxyoctadec-6-enoic acid in optically pure form and determined the absolute configuration of the natural product on the basis of the stereodetermined chiral building block 7, which was prepared by the catalytic enantioselective allylic oxidation of 4,5-epoxycyclohex-1-ene using an S-configured N,N-bidentate ligand-copper catalyst.

Synthesis of Novel Chiral Diamino Alcohols and Their Application in Copper-Catalyzed Asymmetric Allylic Oxidation of Cycloolefins

Optically active amino alcohols are one of the important classes of compounds because of their presence in the natural products. They have also found applications as chiral ligands and auxiliaries for a variety of asymmetric reactions. Furthermore, diamino alcohols and their hydroxyldiamide precursors, in particular, are core units in many medicinal compounds such as HIV protease inhibitors A80987 (3), A77003 (4) and lacosamide (5) (Scheme 1). Due to the importance and high efficiency of chiral hydroxyldiamide, chiral amino alcohols and their methoxy analogy, our attention was focused on the development of a simple and efficient method to produce a small library of enantiomerically pure diamino alcohols 1 and their hydroxyldiamide precursors 2 from readily available starting materials. Although the asymmetric synthesis of vicinal amino alcohols has been extensively studied, however, there have been a few reports of asymmetric synthesis to diamino alcohols, which may become precursors of new kinds of amino alcohol compounds. The chiral hydroxyldiamides 2, which appear structurally similar to molecules 3-5, can be expected to provide more opportunities for the development of biologically active compounds. Moreover, the chiral diamino alcohols, 1, can be used in the asymmetrical reactions as a catalyst to increase reaction rate and as a chiral auxiliary or chiral ligand to induce the chirality in the synthesis of chiral products. Enantioselective allylic oxidation of olefins using copper chiral complexes have been the subject of great interest during the last decade. This reaction provides an access to chiral allylic alcohols, which are the key intermediates in natural products synthesis. Since the use of chiral amino alcohol ligands has been less studied on asymmetric Kharasch reaction, our increasing interest was concentered on the demonstration of catalytic and asymmetric effects of the chiral tridentate diamino alcohols 1 in the asymmetric copper-catalyzed allylic oxidation of cycloolefins. To the best of our knowledge, all the reported allylic oxidations suffer from at least one disadvantage in terms of long reaction times, unsatisfactory yields, or low enantioselectivities. Apparently, yields and ees achieved in this work are superior for the allylic oxidation of cycloolefins in comparison with other works that used chiral amino alcohols as ligands.

ChemInform Abstract: Copper‐Catalyzed Enantioselective Allylic Oxidation of Acyclic Olefins.

AbstractUnsymmetrical peroxides (II) are tested under optimized conditions.

Copper-catalyzed enantioselective allylic oxidation of acyclic olefins

A copper-catalyzed asymmetric allylic oxidation of acyclic olefins has been developed. By using the complexes of copper and chiral spiro bisoxazoline ligands as catalysts, the oxidation of various acyclic olefins was accomplished with excellent regioselectivity (>20:1 in most cases) and up to 67% ee under mild reaction conditions, which represents one of the best results for the enantioselective allylic oxidation of acyclic olefins.

Chiral bisoxazoline ligands with a biphenyl backbone: development and application in catalytic asymmetric allylic oxidation of cycloolefins

A simple and efficient method for the synthesis of chiral biphenylbisoxazoline ligands was developed. The bishydroxylamide precursors of ligands showed a dynamic atropselective resolution effect in the crystallization process. When biphenylbisoxazoline ligands were coordinated to tetrakis(acetonitrile)copper(I) hexafluorophosphate, it resulted in the formation of only a single diastereomer complex (S,aS,S), which behaved as a catalyst for the enantioselective allylic oxidation of cycloolefins. The enantioselectivity, yield, and rate of this reaction were optimized under different conditions, such as a change of solvents, temperature, and additives and also using various copper salts. The use of SBA-15 mesoporous silica as an additive played a crucial role in increasing the efficiency of the reaction.

ChemInform Abstract: Chiral 2,6‐Bis(5′,5′‐diphenyloxazoline)pyridine as an Efficient Ligand for Asymmetric Catalysis

AbstractReview: 29 refs.

Chiral 2,6-bis(5',5'-diphenyloxazoline)pyridine as an efficient ligand for asymmetric catalysis

A modified tridentate pyridine bisoxazoline (pybox) ligand, possessing gem-diphenyl substitution at C-5 of the oxazoline rings, has been proved to be a very efficient ligand for enantioselective allylic oxidation, one-pot three-component synthesis of propargy-amines, and Friedel–Crafts alkylation of various aromatic compounds. We have shown that a 5',5'-diphenyl grouping in the oxazoline rings of chiral ligands is crucial for higher reaction rates as well as enhanced enantioselectivity.

ChemInform Abstract: Asymmetric Kharasch Reaction: Catalytic Enantioselective Allylic Oxidation of Olefins Using Chiral Pyridine Bis(diphenyloxazoline)-Copper Complexes and tert-Butyl Perbenzoate.

Copper complexes of chiral pyridine bis(diphenyloxazoline)-type ligands have been studied as catalysts for the enantioselective allylic oxidation of olefins. Using 2.5−5 mol % of these chiral catalysts and tert-butyl perbenzoate as oxidant, optically active allylic benzoates were obtained in up to 86% ee. A variety of copper salts was studied under different conditions and in different solvents. Acetone was found to be a superior solvent for the reaction. Use of phenylhydrazine in conjunction with the chiral copper complex played a crucial role in increasing the rate of the reaction. Use of 4 A molecular sieves increased the optical yield of product in almost every case.

Asymmetric desymmetrization of 4,5-epoxycyclohex-1-ene by enantioselective allylic oxidation.

Asymmetric desymmetrization of allylic oxidation of 4,5-epoxycyclohex-1-ene (1) took place in the presence of 2.5 mol % of Cu(CH(3)CN)(4)PF(6) and 3 mol % of chiral N,N-bidentate ligand (S)-2 to afford (3S,4S,5S)-3-benzoyloxy-4,5-epoxycyclohex-1-ene (3) in 84% ee, which was increased up to >99% ee after recrystallization of 3-4'-nitrobenzoyloxy derivative 6. Optically pure 6 proved to be a key intermediate for enantioselective synthesis of O-protected 2-deoxystreptamine (2-DOS) precursor 12.

Studies on Enantioselective Allylic Oxidation of Olefins Using Peresters Catalyzed by Cu(I)‐Complexes of Chiral Pybox 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, please click on HTML or PDF.

Enantioselective oxidation of olefins catalyzed by chiral copper bis(oxazolinyl)pyridine complexes: a reassessment

Copper complexes of chiral tridentate pybox ligands synthesized using a modified procedure have been studied as catalysts for the enantioselective allylic oxidation of olefins. A variety of olefins have been used in this reaction. Using 5 mol% of a Cu(II) complex of the tridentate pybox ligand, phenylhydrazine, and tert-butyl perbenzoate as oxidant in acetone, optically active allylic benzoates were obtained up to 94% ee in few hours. It was also observed that the use of molecular sieves in the reaction did not alter the enantioselectivity. Temperature was found to be very crucial in rate of the enantioselective allylic oxidation of olefins. Using EPR spectra, it has been shown that the Cu(II) species is reduced to Cu(I) by phenylhydrazine and phenylhydrazone, but the reduction with the former is faster in comparison to the latter. It was concluded that the rate enhancement was not specific to the presence of phenylhydrazine or phenylhydrazone, but both were equally responsible provided acetone was used as a solvent.

Studies on enantioselective allylic oxidation of olefins using peresters catalyzed by Cu(i)-complexes of chiral pybox ligands

Enantioselective allylic oxidation of olefins with various peresters, using a catalytic amount of Cu(I)-pybox complex, can be tuned to achieve high asymmetric induction (up to 98% ee) by choosing a unique combination of a ligand and a perester at room temperature. The asymmetric induction in the reaction strongly depends on the nature of the substituents attached to the aryl ring of peresters. The presence of a gem-diphenyl group at C-5 and secondary or tertiary alkyl substituents at the chiral center (C-4) of the oxazoline rings is crucial for high enantioselectivity. A pi-pi stacking model has been proposed and discussed to explain the stereochemical outcome of the reaction.

New chiral bidentate ligands containing thiazolyl and pyridyl donors for copper-catalyzed asymmetric allylic oxidation of cyclohexene

Chiral bidentate ligands 1– 3, which contain a combination of thiazolyl and pyridyl donors units, were prepared. The syntheses are facile and being based on Kröhnke condensation of a pinene derivative to form the pyridine ring. Modification at the 8-position of the tetrahydroquinoline ring can be carried out by alkylation reaction with 2a and 3a but not 1a. The structure of a copper(II) perchlorate complex of 1a was characterized with X-ray crystallography, which reveals the binding of the pyridyl–thiazole as a N– N donors at the copper center. The copper(I) thiazolyl–pyridine complexes prepared in situ are active catalysts in the enantioselective allylic oxidation of cyclohexene using tert-butyl perbenzoate as the oxidant. The isolated yields of the allylic benzoate were up to 98%, and enantioselectivity was up to 62% e.e.

Chiral bipyridine–copper(I) complex-catalyzed enantioselective allylic oxidation of cyclic alkenes

Chiral copper(I)–bipyridine complexes were prepared and used as catalysts in the enantioselective allylic oxidation of cyclic alkenes with tert-butyl perbenzoate. The yields ranged from moderate to good and enantioselectivities up to 70% were observed.

Enantioselective Allylic Oxidation of Olefins Using Chiral Quinolinyl‐oxazoline Copper Complex Catalysts

AbstractCopper complexes of chiral quinolinyl‐oxazoline have been studied as the catalysts for enantioselective allylic oxidation of cycloalkenes with tert‐butyl perbenzoate. Using 5 mol% of these chiral catalysts, optical active allylic benzoates were obtained in moderate enantiomeric excesses. CuOTf prepared in situ, CuClO4 and CuPF6 were found to be good precatalysts in acetone.

Asymmetric Kharasch Reaction: Catalytic Enantioselective Allylic Oxidation of Olefins Using Chiral Pyridine Bis(diphenyloxazoline)−Copper Complexes and tert-Butyl Perbenzoate,

Copper complexes of chiral pyridine bis(diphenyloxazoline)-type ligands have been studied as catalysts for the enantioselective allylic oxidation of olefins. Using 2.5−5 mol % of these chiral catalysts and tert-butyl perbenzoate as oxidant, optically active allylic benzoates were obtained in up to 86% ee. A variety of copper salts was studied under different conditions and in different solvents. Acetone was found to be a superior solvent for the reaction. Use of phenylhydrazine in conjunction with the chiral copper complex played a crucial role in increasing the rate of the reaction. Use of 4 A molecular sieves increased the optical yield of product in almost every case.