Oxazoline Ring Research Articles

Chiral Oxazoline‐1,3‐dithianes: New Effective Nitrogen—Sulfur Donating Ligands in Asymmetric Catalysis.

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Triruthenium carbonyl clusters derived from chiral aminooxazolines: synthesis and catalytic activity

Treatment of [Ru3(CO)12] with the chiral aminooxazolines (+)-2-amino-(4R)-phenyl-2-oxazoline (H2amphox), (+)-2-amino-(4R,5S)-indanyl-2-oxazoline (H2aminox) and (+)-2-(2-anilinyl)-(4R,5S)-indanyl-2-oxazoline (H2aninox) in THF at reflux temperature, affords the complexes [Ru3(mu-H)(mu3-kappa2-Hox-N,N)(CO)9] (H2ox = H2amphox, 1; H2aminox, 2) and [Ru3(mu-H)(mu-kappa2-Haninox-N,N)(CO)9] (3). In all cases, the activation of an N-H bond has occurred and the resulting amido fragment spans an edge of the metal triangle, while the N atom of the oxazoline ring is attached to the remaining metal atom (as in 1 and 2), or to one of the metal atoms of the bridged edge (as in 3). The use of 1-3 as catalyst precursors in the asymmetric hydrogen-transfer reduction of acetophenone and in the asymmetric cycloaddition of cyclopentadiene and acroleine is reported.

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.

Conformational Preferences and Enantiodiscrimination of Phosphino-4-(1-hydroxyalkyl)oxazoline−Metal−Olefin Complexes Resulting from an OH−Metal Hydrogen Bond

[reaction: see text] Phosphinooxazolines carrying (1-hydroxy-1-phenyl)methyl and (1-methoxy-1-phenyl)methyl substituents in the 4 position of the oxazoline ring exhibit contrasting behavior in Pd- and Ir-catalyzed allylic alkylations. Whereas catalysts with the methoxy-containing ligand generally provide products with high ee's, use of catalysts prepared from the hydroxy-containing ligand results in products with low ee's or even racemates. DFT calculations suggest the presence of a hydrogen bond with Pd(0) as the proton acceptor in the hydroxy-containing olefin-Pd(0) complexes, which induces a conformational change in the ligand, leading to different stereoselectivity.

Observed Instability of Bound Pybox Ligands towards Acetate Counterions

Reaction of Pd(OAc)2 with bis(oxazolinyl)pyridine (pybox) ligands led cleanly to products that contained a ring-opened oxazoline ring. The transformations were formally the result of the attack of bound pybox ligands by acetate counterions, leading to acetate incorporation into the ring-opened products.

Total Synthesis of Halipeptins: Isolation of Halipeptin D and Synthesis of Oxazoline Halipeptin Analogues

The isolation from the marine sponge Leiosella cf. arenifibrosa and structural elucidation of halipeptin D (5), a relative of the previously isolated halipeptins A-C (1-3), is described along with the total synthesis of a number of oxazoline analogues (7 a-d and epi-7 c-d). The developed synthetic strategy provides a flexible entry into the various isomers of the polyketide domain of the halipeptins and improvises for a late stage construction of the oxazoline ring after a macrolactamization process which secures the required macrocycle.

Chiral oxazoline-1,3-dithianes: new effective nitrogen–sulfur donating ligands in asymmetric catalysis

A series of new chiral oxazoline-1,3-dithianes has been easily synthesized and used as ligands for asymmetric catalysis. The conjugate addition of Et 2Zn to enones resulted in ees of up to 69%, whereas the Pd-catalyzed allylic alkylation led to the expected products in almost quantitative yields and up to 90% enantioselectivity. The ligand’s conformation has been explored using a combination of X-ray and NMR measurements, indicating the presence of a remarkable anomeric effect, which accounts for the preference of the oxazoline ring for the axial location.

Three isomeric forms of hydroxyphenyl-2-oxazoline: 2-(2-hydroxyphenyl)-2-oxazoline, 2-(3-hydroxyphenyl)-2-oxazoline and 2-(4-hydroxyphenyl)-2-oxazoline

Crystal structures are reported for three isomeric compounds, namely 2-(2-hydroxyphenyl)-2-oxazoline, (I), 2-(3-hydroxyphenyl)-2-oxazoline, (II), and 2-(4-hydroxyphenyl)-2-oxazoline, (III), all C9H9NO2 [systematic names: 2-(4,5-dihydro-1,3-oxazol-2-yl)phenol, (I), 3-(4,5-dihydro-1,3-oxazol-2-yl)phenol, (II), and 4-(4,5-dihydro-1,3-oxazol-2-yl)phenol, (III)]. In these compounds, the deviation from coplanarity of the oxazoline and benzene rings is dependent on the position of the hydroxy group on the benzene ring. The coplanar arrangement in (I) is stabilized by a strong intramolecular O-H...N hydrogen bond. Surprisingly, the 2-oxazoline ring in molecule B of (II) adopts a 3T4 (C2TC3) conformation, while the 2-oxazoline ring in molecule A, as well as that in (I) and (III), is nearly planar, as expected. Tetramers of molecules of (II) are formed and they are bound together via weak C-H...N hydrogen bonds. In (III), strong intermolecular O-H...N hydrogen bonds and weak intramolecular C-H...O hydrogen bonds lead to the formation of an infinite chain of molecules perpendicular to the b direction. This paper also reports a theoretical investigation of hydrogen bonds, based on density functional theory (DFT) employing periodic boundary conditions.

Bioisosteric phentolamine analogs as potent α-adrenergic antagonists

The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds ( 2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat α 1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human α 1- and α 2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the α 2- versus the α 1-ARs, affinities being the least at the α 1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six α-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human α 1A- and α 2A-AR subtypes indicate that a basic functional group is important for optimum binding to the α 1- and α 2A-adrenergic receptors.

Asymmetric Cyclopropanation of 2,5‐Dimethyl‐2,4‐hexadiene by Copper Catalysts Bearing New Bisoxazoline Ligands.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Novel chiral bis(oxazolines): synthesis and application as ligands in the copper-catalyzed enantioselective conjugate addition of diethylzinc to enones

Novel chiral C 2-symmetric bis(oxazolines) were prepared from tartaric acid. They were applied as ligands in the copper-catalyzed conjugate addition of diethylzinc to chalcone and 2-cyclohexenone. Maximum enantiomeric excesses of 50% and 53% were obtained, respectively. The sense of induction was found to depend on the configuration of the stereogenic centre in the oxazoline ring, and not on the stereogenic centres of the 1,4-dioxane backbone.

Chiral Phosphinophenyloxazolines Bearing Alkoxymethyl Substituents: Synthesis and Application in the Palladium Catalyzed Allylic Substitution Reactions

The chiral phosphine-oxazoline ligands 3 and 4 bearing 4-alkoxymethyl substituents on the oxazoline ring with (R)-configuration were prepared from L-serine methyl ester in 66% and 33% yields, respectively. Along this synthetic pathway, the β-hydroxylamides derived from L-serine methyl ester and 2-halobenzoyl chlorides were expediently converted to the corresponding oxazolines by using diethylaminosulfur trifluoride as the activation agent. Potassium diphenylphosphide was the reagent of choice for replacing the bromine atom on the phenyl ring, giving the desired oxazoline-phosphine ligands 3 and 4. Together with [Pd(η3-allyl)Cl]2, ligands 3 and 4 induced an enantioselective allylic substitution reaction of 1,3-diphenyl-2-pro-penyl acetate by dimethyl malonate. Although ligands 3 and 4 exhibit the (R)-configuration, differing from the (S)-configuration of Pfaltz-Helmchen-Williams phosphine-oxazoline ligands, all these ligands led to the same enantiotopic preference in the allylic substitution reaction. To facilitate the recovery and reuse of the phosphine-oxazoline ligand, immobilization on Merrifield resin was attempted, albeit in low loading.

An Efficient, Stereocontrolled Synthesis of a Potent Omuralide−Salinosporin Hybrid for Selective Proteasome Inhibition

A short and highly stereocontrolled synthesis of the potent proteasome inhibitor 3 from the (S)-threonine-derived oxazoline 4 has been developed. The synthetic sequence is summarized in Scheme 1. Aldol coupling of the zinc enolate of 4 with isobutyraldehyde and subsequent silylation provided the TBS ether 5 diastereoselectively (10:1). Reductive cleavage of the oxazoline ring of 5 followed by Swern oxidation of the resulting amino alcohol afforded amino ketone 6, converted further by N-acylation to the acrylamide 7, whose structure was confirmed by X-ray crystallographic analysis. Acrylamide 7 was cyclized to 8 by a novel application of the Kulinkovich Ti(II)-cyclopentene complex. Silylation of 8 to 9 and radical cyclization at low temperature produced the bicyclic lactam 10 with complete control of all stereocenters. Hydroxy desilylation and N-deprotection of 10 gave the dihydroxy ester 11, which was converted to 3 by a novel three-step sequence: (1) demethylation with [Me2AlTeMe]2, (2) combined beta-lactonization and chlorination, and (3) desilylation to effect cleavage of the TBS ether.

Patellamide A and C biosynthesis by a microcin-like pathway inProchloron didemni, the cyanobacterial symbiont ofLissoclinum patella

Prochloron spp. are obligate cyanobacterial symbionts of many didemnid family ascidians. It has been proposed that the cyclic peptides of the patellamide class found in didemnid extracts are synthesized by Prochloron spp., but studies in which host and symbiont cells are separated and chemically analyzed to identify the biosynthetic source have yielded inconclusive results. As part of the Prochloron didemni sequencing project, we identified patellamide biosynthetic genes and confirmed their function by heterologous expression of the whole pathway in Escherichia coli. The primary sequence of patellamides A and C is encoded on a single ORF that resembles a precursor peptide. We propose that this prepatellamide is heterocyclized to form thiazole and oxazoline rings, and the peptide is cleaved to yield the two cyclic patellamides, A and C. This work represents the full sequencing and functional expression of a marine natural-product pathway from an obligate symbiont. In addition, a related cluster was identified in Trichodesmium erythraeum IMS101, an important bloom-forming cyanobacterium.

Asymmetric Cyclopropanation of 2,5-Dimethyl-2,4-hexadiene by Copper Catalysts Bearing New Bisoxazoline Ligands

Some new bisoxazoline ligands with an aryl group at the 4-position and gem-dimethyl groups at the 5-position on the oxazoline ring were prepared from arylglycines. Remarkable enhancement of the trans-selectivity (trans/cis = 87/13) and the enantioselectivity (96% ee for the trans product) was demonstrated for the asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene with tert-butyl diazoacetate catalyzed by the new copper-bisoxazoline complex.

Development of a Novel Chiral Spiro Ligand Bearing Oxazoline.

Abstract The synthesis of bis(oxazoline) ligand 1 bearing a spiro skeleton is achieved via double ring-closing metathesis (RCM) of tetraene 2 and subsequent oxazoline ring formation using N-bromosuccinimide (NBS). The Cu-spiro bis(oxazoline) complexes prepared from 1 and Cu(OTf)2 or Cu(OAc)2 act efficiently as chiral catalysts for promoting carbonyl-ene reactions or Henry reactions with good enantiocontrol.

Organosilanols as Catalysts in Asymmetric Aryl Transfer Reactions

[reaction: see text] Various ferrocene-based organosilanols have been synthesized in four steps starting from achiral ferrocene carboxylic acid. Applying these novel planar-chiral ferrocenes as catalysts in asymmetric phenyl transfer reactions to substituted benzaldehydes afforded products with high enantiomeric excesses. The best result (91% ee) was achieved in the addition to p-chlorobenzaldehyde with organosilanol 2b, which has a tert-butyl substituent on the oxazoline ring and an isopropyl group on the silanol fragment.

New Chiral Ligands Derived from Mandelic Acid: Synthesis and Application in the Asymmetric Phenyl Transfer Reaction to an Aromatic Aldehyde.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Efficient and General One-Pot Method for the Synthesis of Chiral Bis(oxazoline) and Pyridine Bis(oxazoline) Ligands

Abstract: An expeditious method for the synthesis of chiral boxand pybox ligands is reported. The approach is based on a one-potcondensation reaction of chiral b-amino alcohols with a dinitrileusing stoichiometric or catalytic amounts of zinc triflate. Yieldsgreater than 90% are obtained in many cases without the need forfurther purification of the product. Key words: bis(oxazolines), pybox, synthesis, zinc triflate, tolu-ene, chiral ligands Chiral bis(oxazolines) (box) are widely used in the asym-metric catalysis of an increasing variety of organic reac-tions including cyclopropanations, Diels–Alder, ene,aziridination, allylic substitutions, Mukaiyama–Michael,Mukaiyama aldol reactions, 1,2 to mention just a few. Boxsystems bearing a one-carbon spacer between the twooxazoline rings are the most frequently used.Since 1997 many attempts have also been made to supportbox ligands in heterogeneous systems. 3 The introduction of a third coordinating atom into the linkbetween the two oxazoline rings has led to the develop-ment of tridentate bis(oxazoline) ligands, among whichpyridine bis(oxazoline) (pybox) derivatives represent thebest known examples. These ligands have been success-fully used in the same types of reactions as bis(oxazol-ines),

Chiral Bis(N-sulfonylamino)phosphine- and TADDOL-Phosphite-Oxazoline Ligands: Synthesis and Application in Asymmetric Catalysis

A series of N,P-ligands has been prepared, containing a chiral oxazoline ring and as a second chiral unit a bis(N-sulfonylamino)phosphine group embedded in a diazaphospholidine ring or a cyclic phosphite group derived from TADDOL. These modular ligands are readily synthesized from chiral amino alcohols and chiral 1,2-diamines or TADDOLs. Palladium and iridium complexes derived from these ligands were found to be efficient catalysts for enantioselective allylic alkylation and olefin hydrogenation, respectively.