Efficient Chiral Auxiliary Research Articles

Regioselective Short Synthesis of Epiisoborneol Neopentyl Ether as Chiral Auxiliary: An Absolute Configuration Reset

AbstractThe regio‐selective four step synthesis of (1S,2R,3S,4R)‐4,7,7‐trimethyl‐3‐(neopentyloxy)bicyclo[2.2.1]heptan‐2‐ol, as recognized efficient chiral auxiliary, is presented. The strategy based on opening of the key acetal 15 (=(2S,3aR,4S,7R,7aS)‐2‐tert‐butyl‐4,8,8‐trimethylhexahydro‐2H‐4,7‐methano‐1,3‐benzodioxole) thus circumvents the poor reactivity of the neopentyl electrophile under alkylation conditions. Following the same strategy, but using the unreported acetal 22 (=(2R,3aS,4S,7R,7aR)‐2‐tert‐butyl‐4,8,8‐trimethylhexahydro‐2H‐4,7‐methano‐1,3‐benzodioxole), the corresponding unreported bis‐endo alcohol 23 (=(1R,2R,3S,4S)‐3‐(2,2‐dimethylpropoxy)‐4,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐ol) could be isolated only in poor yield. An alternative regioselective synthesis, including an ultimate endo‐reduction remains to be found. Several erroneous chiroptical properties from the literature are corrected.

Transition metal-catalyzed asymmetric carbene insertion for synthesis of chiral amines

Chiral amines are an important class of organic compounds. They are ubiquitous in organic chemistry and often serve as fundamental building blocks, versatile synthons, efficient chiral catalysts, ligands or auxiliaries in asymmetric synthesis and medicinal chemistry. During the past few decades, there has been remarkable progress in the development of efficient asymmetric methods. Accordingly, asymmetric synthesis, particularly catalytic enantioselective synthesis of chiral amines has received considerable attention from both academia and industry. Among them, transition metal-catalyzed asymmetric carbene insertion has emerged as one of the most useful and powerful methods for synthesis of various chiral amines through the efficient construction of the C−N bonds. In this review, we present the progress and advances that have been made using copper, rhodium, palladium, and iron catalysts to perform enantioselective N−H insertion reactions with diazo compounds. An overview of early examples of Cu(I) and Ag(I)-bisoxazoline-catalyzed asymmetric N−H insertion and the subsequent developments by using copper(I) complexes with chiral spiro bisoxazolines, bipyridines and binol derivatives, as well as with rhodium(II)-, palladium(II)-, iron(II)-carbene chemistry is provided. In these work, catalytic asymmetric metal-carbene insertion into the N−H bond of aromatic amines, amides (BocNH2, CbzNH2), substituted carbazoles and indoles, and benzophenone imines were achieved under mild reaction conditions, allowing access to a wide variety of structurally important chiral amines in enantiomerically enriched form. In particular, with the use of α-aryl or α-alkyl α-diazoesters as carbene precusors, both aryl and alkyl substituted α-amino esters could be prepared in good yields with high enantioselectivities. A recent major breakthrough in enantioselective transition-metal-catalyzed N−H insertion reactions with aliphatic amines is also discussed. By using a combination of an achiral copper complex and chiral amino-thiourea catalyst, highly enantioselective carbene insertion into N−H bonds of aliphatic amines was achieved to produce various chiral α-alkyl α-amino acid derivatives bearing secondary and tertiary amino substituents in good yields. Overall, this review summarizes the most prominent work on transition-metal-catalyzed asymmetric carbene N−H insertion and their applications in chiral amines and natural or unnatural chiral α-amino acid derivatives synthesis.

Enantiopure 4-oxazolin-2-ones and 4-methylene-2-oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles.

Enantiopure 3-((R)- and 3-((S)-1-phenylethyl)-4-oxazoline-2-ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N-(R)- or N-(S)-1-phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4- and 5-positions of the 4-oxazolin-2-one ring through thermal and MW-promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six-membered carbo- and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4-methylene-2-oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero-Diels-Alder cycloaddition.

Enantiomerically Pure [2.2]Paracyclophane-4-thiol: A Planar Chiral Sulfur-Based Building Block Readily Available by Resolution with an Amino Acid Chiral Auxiliary.

Acyl chloride of N-phthaloyl-(S)-isoleucine is an efficient chiral auxiliary for the resolution of (±)-[2.2]paracyclophane-4-thiol. A preparative protocol, based on the conversion into diastereoisomeric thiolesters and separation by two fractional crystallizations and column chromatography, was developed. Deprotection with LiAlH4 allowed isolation of the individual thiol enantiomers in good yield (∼40%) and high enantiomeric purity (ee >93%). The absolute configurations were determined by comparison of the optical rotation value of the products with literature data and were confirmed by X-ray crystallography.

ChemInform Abstract: Endo‐Benzonorbornen‐2‐ol as an Efficient Non‐natural Chiral Auxiliary in the Asymmetric aza‐Diels—Alder Reactions Between Cyclopentadiene and (1‐Phenylethyl)iminoacetates.

Exo-2-azabicyclo[2.2.1]hept-5-enes were obtained by cycloaddition reactions between cyclopentadiene and protonated (S)- and (R)-1-phenylethylimines of (1R,endo)-benzonorbornen-2-yl glyoxylate. The non-natural (1R,endo)-benzonorbornen-2-ol proved to be an efficient chiral auxiliary in these asymmetric aza-Diels–Alder reactions, which afforded only exo-cycloadducts with 1S : 1R diastereomeric ratios of 15 : 85 for (S)-(1-phenylethyl)imine and 93 : 7 for (R)-(1-phenylethyl)imine. The obtained diastereoisomers were effortlessly and efficiently isolated using a chromatographic column. The absolute configuration of all the formed adducts was unequivocally assigned through NMR, specific optical rotation and X-ray data.

ChemInform Abstract: Recent Advances in the Application of the Oppolzer Camphorsultam as a Chiral Auxiliary

AbstractReview: [147 refs.

Endo-benzonorbornen-2-ol as an efficient non-natural chiral auxiliary in the asymmetric aza-Diels–Alder reactions between cyclopentadiene and (1-phenylethyl)iminoacetates

Exo-2-azabicyclo[2.2.1]hept-5-enes were obtained by cycloaddition reactions between cyclopentadiene and protonated (S)- and (R)-1-phenylethylimines of (1R,endo)-benzonorbornen-2-yl glyoxylate. The non-natural (1R,endo)-benzonorbornen-2-ol proved to be an efficient chiral auxiliary in these asymmetric aza-Diels–Alder reactions, which afforded only exo-cycloadducts with 1S : 1R diastereomeric ratios of 15 : 85 for (S)-(1-phenylethyl)imine and 93 : 7 for (R)-(1-phenylethyl)imine. The obtained diastereoisomers were effortlessly and efficiently isolated using a chromatographic column. The absolute configuration of all the formed adducts was unequivocally assigned through NMR, specific optical rotation and X-ray data.

ChemInform Abstract: Asymmetric Mannich Reactions of Imidazo[2,1‐b]thiazole‐derived Nucleophiles with (Ss)‐N‐tert‐Butanesulfinyl (3,3,3)‐Trifluoroacetaldimine.

AbstractIn the title reaction, the N‐tert‐butylsulfinyl group serves not only as an efficient chiral auxiliary, but also as an amine protecting group.

ChemInform Abstract: An Efficient Asymmetric Synthesis of 1-Acyl-2-alkyl-1,2- dihydropyridines.

Two efficient chiral auxiliary mediated asymmetric syntheses of synthetically useful 1-acyl-2-alkyl-1,2-dihydropyridines are described.

ChemInform Abstract: Chiral Hexacoordinated Phosphorus Anions: Effective Auxiliaries for Anion Mediated Asymmetric Processes

Easily synthesized and resolved TRISPHAT anion is an efficient chiral auxiliary for asymmetric processes with chiral cations.

ChemInform Abstract: The 2-(N,N-Dimethylamino)phenylsulfinyl Group as an Efficient Chiral Auxiliary in Intramolecular Heck Reactions.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.

ChemInform Abstract: Asymmetric Allylic Oxidation of Cycloalkenes Using a Tridentate Tris(oxazoline) Ligand as a Chiral Auxiliary.

Abstract A tridentate tris(oxazoline) ligand (4b) was found to be an efficient chiral auxiliary for copper-mediated asymmetric allylic oxidation (Kharash–Sosnovsky reaction) of cycloalkenes. Regardless of the ring size of the substrate, the reaction examined showed good enantioselectivity higher than 81% ee.

ChemInform Abstract: Axial Chirality Control During Suzuki—Miyaura Cross‐Coupling Reactions: The tert‐Butylsulfinyl Group as an Efficient Chiral Auxiliary.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 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.

Axial Chirality Control During Suzuki−Miyaura Cross-Coupling Reactions: The tert-Butylsulfinyl Group as an Efficient Chiral Auxiliary

An efficient route to a new family of axially chiral biaryl ligands by a Suzuki-Miyaura cross-coupling reaction between ortho,ortho'-disubstituted aryl iodides bearing in ortho position a tert-butyl or p-tolylsulfinyl group and ortho-substituted phenyl boronic acids or esters is described. The comparison between the t-BuSO and p-TolSO groups as chiral controllers is reported. The modularity of the approach is demonstrated by the preparation of a variety of enantiopure axially chiral mixed S/N and S/P ligands.

Construction of a new type of chiral bidentate NHC ligands: copper-catalyzed asymmetric conjugate alkylation

We synthesized in three steps simple chiral bidentate NHC compounds that carry an achiral coordinating group as N-substituent and revealed that they serve as efficient chiral auxiliaries for the copper-catalyzed asymmetric conjugate addition of dialkylzinc to acyclic enones (up to 97% ee).

( R)-4-phenyloxazolidin-2-thione: an efficient chiral auxiliary for [4+2] cycloaddition of 1-aminodiene and activated phosphonodienophiles

A theoretical model for the facial selectivity of N-dienyl oxazolidin-2-(thi)one and thiazolidin-2-thione 2a– c is presented. Our analysis provides a clear understanding of factors controlling stereoselectivity in reaction of these dienes, and allows predictions of high diastereoselectivity in the case of oxazolidin-2-thionyl diene ( 2b). The application of this diene to the synthesis of β- and γ-aminophosphonic derivatives is then investigated. Under classical conditions or under microwave activation, the D–A reaction of diene 2b leads to aminophosphonic chirons with high regio- and stereoselectivities.

Efficient preparation of chiral non-racemic sulfur compounds

p-Menthane-3-carboxaldehyde serves as an efficient chiral auxiliary in the preparation of chiral non-racemic S-alkylthiocarbamates or S-dithiocarbonates via the 3,3-sigmatropic rearrangement of the corresponding alkylthionocarbamates or xanthates. The transfer of chirality during rearrangement is complete, and the final products possess a chiral tertiary or quaternary carbon bearing sulfur. The rearranged products are then transformed into enantiopure cyclic or acyclic sulfur-containing products, depending on the means of clivage of the auxiliary. The synthesis of a potent MMP-13 inhibitor is presented.Key words: 3,3-sigmatropic rearrangement, p-menthane-3-carboxaldehyde, S-alkylthiocarbamate, S-dithiocarbonate, alkylthionocarbamate, xanthate, ring-closing metathesis.

Synthesis of a New (1R)-(−)-Myrtenal-Derived Dioxadithiadodecacycle and Its Use as an Efficient Chiral Auxiliary

[reaction: see text] The new macrocycle 9 (>70% yield from hydroxythiol 10) was treated with several nucleophilic reagents (RMgX, RLi, and LiAlH4) affording carbinols 12a-j (80-96% yield, >99:1 dr). Oxidative hydrolysis of 12a,c,e, followed by LiAlH4 reduction of the resulting mixture, gave 16a,c,e in >95% ee,16c being a key precursor for the preparation of fungicide 17. The absolute configuration of 9 and 12j (Nu = H) was established by single-crystal X-ray diffraction analyses and chemical correlation.

Enantioselective Conjugate Addition of Diethylzinc to Acyclic Enones Using a Copper Phosphino‐Phenol Complex as Catalyst.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective conjugate addition of diethylzinc to acyclic enones using a copper phosphino-phenol complex as catalyst

Newly designed phosphino-phenol 1c was found to be an efficient chiral auxiliary for copper-mediated asymmetric conjugate addition of diethylzinc to acyclic enones. High enantioselectivity up to >99% ee was achieved in the reaction of acyclic α,β-enones.