β-Arylation of Racemic Secondary Benzylic Alcohols to Access Enantioenriched β-Arylated Alcohols

The transformation of alcohols into value-added products is of great importance, as simple alcohols are widespread and can be easily derived from both fossil fuels and biomass. The selective functionalization of a sp³ C−H bond on the alkyl side chain of an alcohol over its hydroxyl group would offer an expedient route to expand the chemical space of alcohols but it remains a challenging task. Harnessing the borrowing hydrogen strategy, the β-arylation of secondary alcohols with aryl bromides has been achieved in this study, which allows for the selective functionalization of a β-Csp³−H bond in an alcohol substrate. Under the catalysis of a Pd complex, secondary alcohols reacted with aryl bromides to afford 1,2-diaryl alcohols with broad substrate scope in the presence of a ketone additive. Furthermore, the enantioconvergent version of the reaction has also been realized, transforming racemic secondary alcohols into enantioenriched chiral 1,2-diaryl alcohols under the cooperative Pd and Ru catalysis. Mechanism studies indicate that the reactions are enabled by borrowing hydrogen catalysis.     

Asymmetric Addition of Diethylzinc to Aldehydes Catalyzed by Chiral γ_Amino Alcohols

Although the asymmetric additions of diethylzinc to aldehydes have been extensively studied in the presence of chiral catalyst, most of the chiral ligands tested are b-amino alcohols1. In this report, the synthesis of chiral gamino alcohols 1-4 from the reaction of (+)-camphor and (-)-menthone with 2-lithiomethyl-6-methyl-pyridine or 2-picolly- lithium2, which give a single diasteromer as determined by 1H NMR with high yields (Scheme 1)3, and their application in the enantioselective additio…     

Visible-Light-Driven Three-Component Reaction of Unactivated Alkenes Enables Access to Monofluoro γ-Amino Acids

A strategy for the synthesis of diverse protected α-monofluoro-γ-amino acid derivatives has been developed. This reaction assembles a simple enamide, quinoxalin-2(1H)-one, and diethyl 2-bromo-2-fluoromalonate through a three-component reaction driven by visible light. The advantages of this protocol include the simplicity of its operation, mild conditions, high functional group tolerance, and applicability to a wide variety of substrates. The synthesis of this fluorine-containing amino acid derivative has significant value for potential applications in medicinal chemistry and chemical biology.     

Enzymatic Synthesis of Noncanonical α-Amino Acids Containing γ-Tertiary Alcohols

Noncanonical amino acids (ncAAs) containing tertiary alcohols are valuable as precursors of natural products and active pharmaceutical ingredients. However, the assembly of such ncAA scaffolds from simple material by C−C bond formation remains a challenging task due to the presence of multiple stereocenters and large steric hindrance. In this study, we present a novel solution to this problem through highly selective enzymatic decarboxylative aldol addition. This method allows for the streamlined assembly of multifunctionalized ncAAs with γ-tertiary alcohols from readily available materials, such as _L-aspartatic acid and isatins, vicinal diones and keto esters. The modularity of electrophiles furnished four classes of ncAAs with decent efficiency as well as excellent site and stereocontrol. Computational modeling was employed to gain detailed insight into the catalytic mechanism and to provide a rationale for the observed selectivities. The method offers a single-step approach to producing multifunctionalized ncAAs, which can be directly utilized in peptide synthesis and bioactivity assessment.     

Synthesis of Peroxy-Containing Acetylenic Alcohols and Ethers Derived from γ-Amino Ketones

A series of peroxy-containing tertiary alcohols were prepared by the reactions of lithium peroxy acetylenides with -amino ketones. The reactions of the intermediate lithium peroxy alcoholates with alkyl iodides in the presence of hexamethylphosphoramide yielded the corresponding peroxy ethers. The thermal stability of the compounds synthesized was evaluated by thermal analysis.     

Enantioselective Conjugate Addition of Diethylzinc to Chalcone Catalyzed by Ni（acac）2 and Chiralβ-Amino Alcohols

Enantioselectivge conjugate addition of diethyzinc to chalcone was carried out in the presenee of Ni (acac)2 complexed with five pyrrolidfumyimethanois derived from L-proline. (S)-N-Benzyl-2-(l-hydroxy.l-methylethyl) pyrrolidlne was found to be the best ngnd in asymmetric conjugate addition among the five ligands. The products were obtained with up to 70% ee.The configuration of the product was determined jointly by the substituents on the carbon of the hydroxy group and the nitrogen atom.     

Nitrene-Mediated Enantioselective Intramolecular Olefin Oxyamination to Access Chiral γ-Aminomethyl-γ-Lactones

Attaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral-at-ruthenium catalysts, chiral γ-aminomethyl-γ-lactones containing a quaternary carbon in γ-position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ-Aminomethyl-γ-lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ-lactams, 2-oxazolidinones, and tetrahydrofurans.     

Synthesis of New F-Alkyl β-Amino Alcohols

F-alkyl oxiranes 1 and p-methylbenzene sulfonate ester intermediates 3 derived from 2-F-alkyl ethane -1,2-diols 2 are converted into F-alkyl β-amino alcohols 5 respectively by a two-step process.     

Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols

Despite the significant progress of the enantioselective reaction using chiral catalysts, the enantioselective nucleophilic substitution reaction at the chiral sp³-hybridized carbon atom of a racemic electrophile has not been largely explored. Herein, we report the enantioconvergent propargylic substitution reaction of racemic propargylic alcohols with thiols using chiral bis-phosphoric acid as the chiral Brønsted acid catalyst. The substitution products were formed in high yields with high enantioselectivities in most cases. The cation-stabilizing effect of the sulfur functional group introduced at the alkynyl terminus is the key to achieving the efficient enantioconvergent process, in which chiral information originating from not only the racemic stereogenic center but also the formed contact ion pair is completely eliminated from the present system.     

A Regio-and Stereoselective Synthesis of β-Amino Alcohols

The regio-and stereoselective ring opening of epoxide with aromatic amines catalyzed by samarium trichloride and the enantioselective ring opening of cyclohexene oxide with aniline catalyzed by lanthanide complexes were studied.     

Polystyrene-supported Selenides and Selenoxide: Versatile Routes to Synthesize Allylic Alcohols

Combinatorial chemistry and solid phase synthesis have recently emerged as powerful tools for the drug discovery process1. It might be argued that selenoxide syn- elimination provided the principal impetus for the development of organoselenium chemistry. [2, 3] Sigmatropic rearrangement2 of allylic selenium compounds is the most fundamental reaction in the field of synthetic organoselenium chemistry as well as selenoxide syn-elimination. However, organic selenides are highly malodorous and …     

A Convenient Method for the Synthesis of Chiral N-Protected 1, 2-Amino Alcohols via the Reduction of the Aminoketones

A series of optically active N-protected 1,2-amino alcohols were synthesized via the reduction of the corresponding α-aminoketones starting from the readily available L-amino acids.     

Stereoselective Synthesis of δd-Selanyl Allylic Alcohols by Hydrozirconation of Propargyl Selenides

Functionality-bearingallylicalcoholsarethevitalstructureunitsofbiologicallyactivecompounds1,2.Allylicselenidesareimportantintermediatesinorganicsynthesis3,4.Soregio-andstereoselectivesynthesisofd-selanylallylicalcoholwhichcombinetheallylicalcoholandallylicselenideunitstogetherisofinterestinorganicsynthesis.Hydrozirconationhasemergedasauniquehydrometallationwithsomeattractivefeatures5,6.Recentlywehavereportedthestereoselectivesynthesisofa-heteroatomsubstitutedallylicalcoholsbyhydrozirconationof…     

LC Separation of γ-Amino Acid Enantiomers

Three underivatized γ-amino acids were successfully enantioseparated by high-performance liquid chromatography on macrocyclic glycopeptide based chiral stationary phases. The effects of the alcohol modifier in the mobile phase and the column temperature on the enantioseparation were investigated. Apparent thermodynamic parameters were calculated from the plots of ln k or ln α versus 1/T. Some mechanistic aspects of chiral recognition are discussed with respect to the structures of the analytes. It was found that the enantioseparations were enthalpy-driven, the double bond in the analyte exerting a significant influence on the chiral recognition.     

Stereoselective Synthesis of δ-Selanyl Allylic Alcohols by Hydrozirconation of Propargyl Selenides

Hydrozirconation of propargyl selenides afford(E)-3-selanyl vinylzirconocenes chlorides 2.Intermediates 2 reacted with aldehydes to obtain δ-selanyl allylic alcohols.     

Synthesis of a New Chiral Cyclicβ-Amino Alcohol

The enantioselective chiral l,3,2-oxazaborolidine-catalyzed reduction of prochiralketones by borane has been intensively investigated'-'. Most oxazaborolidine catalystshave been prepared from chiral D-amino alcohols. In our previous study on the catalyststructure-enantioselectivity relationships, we prepared (R)-2-amino-1,l-diphenyl-3~(2naphthyl)-l-propanol I which proved to be a good precursor of chiral catalyst for theenantioselective borane reduction of prochiral ketones4-9. This let'ter d…     

Rh‐Catalyzed C?C Cleavage of Benzyl/Allylic Alcohols to Produce Benzyl/Allylic Amines or other Alcohols by Nucleophilic Addition of Intermediate Rhodacycles to Aldehydes and Imines

We report three transformations: 1) direct transformation from biarylmethanols into biarylmethylamines; 2) direct transformation from one biarylmethanol into another biarylmethanol; 3) direct transformation from allylic alcohols into allylic amines. These transformations are based on pyridyl‐directed Rh‐catalyzed C? C bond cleavage of secondary alcohols and subsequent addition to C?X (X=N or O) double bonds. The reaction conditions are simple and no additive is required. The driving force of C? C bond cleavage is the formation of the stable rhodacycle intermediate. Other directing groups, such as the pyrazolyl group, can also be used although it is not as efficient as the pyridyl group. We carried out in‐depth investigations for transformation 1 and found that: 1) the substrate scope was broad and electron‐rich alcohols and electron‐deficient imines are more efficient; 2) as the leaving group, aldehyde had no significant impact on either the C? C bond cleavage or the whole transformation; 3) mechanistic studies (intermediate isolation, in situ NMR spectroscopic studies, competing reactions, isotopic labeling experiments) implied that: i) The C? C cleavage was very efficient under these conditions; ii) there is an equilibrium between the rhodacycle intermediate and the protonated byproduct phenylpyridine; iii) the addition step of the rhodacycle intermediate to imines was slower than the C? C cleavage and the equilibrium between the rhodacycle and phenylpyridine; iv) the whole transformation was a combination of two sequences of C? C cleavage/nucleophilic addition and C? C cleavage/protonation/C? H activation/nucleophilic addition, with the latter being perhaps the main pathway. We also demonstrated the first example of cleavage of an C(alkenyl)? C(benzyl) bond. These transformations showed the exchange (or substitution) of the alcohol group with either an amine or another alcohol group. Like the “group transplant”, this method offers a new concept that can be used to directly synthesize the desired products from other chemicals through reorganization of carbon skeletons.     

Enantioselective Addition of Diethylzinc to Aromatic Aldehydes Catalyzed by Pyrolidine and Piperidine β-Amino Alcohols

The enantioselective alkylation of aryl aldehydes by diethylzinc in the presence of catalytic amounts of several chiral pyrolidine- and piperidine-based amino alcohol ligands, synthesized from the reaction of (R)-2-amino-1-butanol and (S)-2-amino-3-phenylpropan-1-ol with appropriate dibromoalkanes, was studied. The influence of temperature and ligand structure has been investigated. Addition of diethylzinc to aromatic aldehydes under the optimized condition gave the corresponding products in excellent yields with ee values of up to 77%.     

Catalytic Access to Chiral δ-Lactams via Nucleophilic Dearomatization of Pyridine Derivatives

Nitrogen-bearing rings are common features in the molecular structures of modern drugs, with chiral δ-lactams being an important subclass due to their known pharmacological properties. Catalytic dearomatization of preactivated pyridinium ion derivatives emerged as a powerful method for the rapid construction of chiral N-heterocycles. However, direct catalytic dearomatization of simple pyridine derivatives are scarce and methodologies yielding chiral δ-lactams are yet to be developed. Herein, we describe an enantioselective C4-dearomatization of methoxypyridine derivatives for the preparation of functionalised enantioenriched δ-lactams using chiral copper catalysis. Experimental ¹³C kinetic isotope effects and density functional theory calculations shed light on the reaction mechanism and the origin of enantioselectivity.     

(E)-γ-Substituted Allylic Alcohols and α-Substituted Homoallylic Alcohols via Acidic Treatment of the Acetonides Derived from γ-Substituted Vinyl Diols

Treatment of the acetonides of γ-substituted vinyl diols under acidic deprotection conditions afforded γ-substituted allylic alcohols and α-substituted homoallylic alcohols.