Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine.

An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.     

Asymmetric synthesis of dihydro-1,3-dioxepines by Rh(ii)/Sm(iii) relay catalytic three-component tandem [4 + 3]-cycloaddition

Heterocycles have been widely used in organic synthesis, agrochemical, pharmaceutical and materials science industries. Catalytic three-component ylide formation/cycloaddition enables the assembly of complex heterocycles from simple starting materials in a highly efficient manner. However, asymmetric versions remain a yet-unsolved task. Here, we present a new bimetallic catalytic system for tackling this challenge. A combined system of Rh(ii) salt and chiral N,N′-dioxide–Sm(iii) complex was established for promoting the unprecedented tandem carbonyl ylide formation/asymmetric [4 + 3]-cycloaddition of aldehydes and α-diazoacetates with β,γ-unsaturated α-ketoesters smoothly, affording various chiral 4,5-dihydro-1,3-dioxepines in up to 97% yield, with 99% ee. The utility of the current method was demonstrated by conversion of products to optically active multi-substituted tetrahydrofuran derivatives. A possible reaction mechanism was provided to elucidate the origin of chiral induction based on experimental studies and X-ray structures of catalysts and products.

Catalytic asymmetric tandem carbonyl ylide formation/[4 + 3]-cycloaddition of β,γ-unsaturated α-ketoesters, aldehydes and α-diazoacetates was achieved by using a bimetallic rhodium(ii)/chiral N,N′-dioxide–Sm(iii) complex catalyst.     

Trityl Cation-Catalyzed Hosomi-Sakurai Reaction of Allylsilane with β,γ-Unsaturated α-Ketoester to Form γ,γ-Disubstituted α-Ketoesters

(Ph₃C)[BPh(^F)₄]-catalyzed Hosomi-Sakurai allylation of allylsilanes with β,γ-unsaturated α-ketoesters has been developed to give γ,γ-disubstituted α-ketoesters in high yields with excellent chemoselectivity. Preliminary mechanistic studies suggest that trityl cation dominates the catalysis, while the silyl cation plays a minor role.     

Comparison of enantiomer separation on two chiral stationary phases derived from (+)-18-crown-6-2,3,11,12-tetracarboxylic acid of the same chiral selector

Liquid chromatographic comparisons for enantiomer resolution of α-amino acids and chiral primary amino compounds were made using chiral stationary phases (CSPs) prepared by covalently bonding (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (18-C-6-TA) of the same chiral selector. The resolution of all α-amino acids on CSP 1 developed in our group was found to be better than that on CSP 2 reported by Machida et al. All α-amino acids examined in this study were well enantioseparated on CSP 1 (α=1.22–2.47), while four analytes were not resolved or all the other analytes were poorly resolved on CSP 2 than on CSP 1. However, in resolving the primary amino compounds without a carbonyl group, CSP 1 was comparable with CSP 2. Although (+)-18-C-6-TA of the same chiral selector was used to prepare CSP 1 and CSP 2, this study showed that different connecting methods for the CSPs might influence their ability to resolve the analytes depending on their structures related to the chiral recognition mechanism.     

Structural effects in the Pd-induced enantioselective deprotection–decarboxylation of β-ketoesters

Structural effects in the chiral base and the influence of some key reaction parameters (catalyst type and solvent) in the Pd-induced enantioselective decarboxylation (cascade reaction) of three different ,-disubstituted benzyl β-ketoesters were explored. The reaction intermediate after debenzylation (β-keto-carboxylic acid) was synthesized and its decarboxylation studied independently. The highest ee (up to 60%) in the cascade reaction was achieved with those substrates that contained an aromatic ring system and with chiral amino alcohols that possessed an extended aromatic ring (quinine and quinidine). Polar solvents with weak H-bond donor and acceptor properties favor enantioselection.     

BINOL-phosphoric acid catalyzed asymmetric Mannich addition of β-ketoesters to indolenines generated in situ by DDQ

An asymmetric Mannich addition of β-ketoesters to indolenines that were generated in situ from 3-indolinone-2-carboxylates by DDQ has been developed using a catalytic amount of chiral BINOL-phosphoric acid. The corresponding chiral 3-indolinone-2-carboxylate derivatives were obtained in good yields with excellent ee (up to 99%). This is the first report on the enantioselective addition of β-ketoesters to indolenines using a chiral Brønsted acid.     

Synthesis of chiral α-amino acids

A novel method for the synthesis of chiral α-amino acids has been developed where the acid functionality was constructed by oxidizing a hydroxymethyl group introduced by Evans’ method in the α-position of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.     

Stereoselective Copper-Catalyzed Direct Aldol Reaction of β, γ-Unsaturated α-Ketoesters with Coumaran-3-Ones

An efficient direct aldol reaction between coumaran-3-ones and β, γ-unsaturated α-ketoesters by virtue of a chiral copper complex is developed. A series of coumaran-3-one derivatives containing chiral tertiary alcohol structures are obtained in excellent yields and stereoselectivities.     

Construction of a quaternary stereogenic center by asymmetric hydroformylation: a straightforward method to prepare chiral α-quaternary amino acids

The construction of chiral quaternary carbon stereocenters has been a long-standing challenge in organic chemistry. Particularly, α-quaternary amino acids that are of high importance in biochemistry still lack a straightforward synthetic method. We here reported a hydroformylation approach to access chiral quaternary stereogenic centers, which has been a long-standing challenge in transition metal catalysis. α,β-Unsaturated carboxylic acid derivatives undergo hydroformylation with a rhodium catalyst to generate an α-quaternary stereocenter under mild conditions. By using this method, a variety of chiral α-quaternary amino acids could be synthesized with satisfactory enantioselectivity. In-depth investigation revealed that the regioselectivity is dramatically influenced by the electronic properties of the substituents attached to the target C C bond. By applying NMR and DFT analyses, the chiral environment of a rhodium/Yanphos complex was depicted, based on which a substrate-catalyst interaction model was proposed.

A rhodium-catalyzed asymmetric hydroformylation reaction was reported to construct chiral α-quaternary amino acid derivatives. High chemo-, regio- and enantioselectivity were realized in one step.     

Chiral Recognition of Propranolol with <Emphasis Type="Bold">β</Emphasis>-Cyclodextrin in the Presence of 1- and 2-Butanol

The purpose of this work is to investigate the chiral recognition characteristics of β-cyclodextrin with two propranolol enantiomers in the presence of organic additives. Steady-state fluorescence measurements of propranolol β-cyclodextrin (β-CD) complexes were performed for solutions containing either 1- or 2-butanol. For each 2-butanol isomer solution, the interactions were assessed by comparing the changes in the fluorescence of (R)-(+)- propranolol versus (S)-(-)-propranolol as a function of CD concentration. A similar comparison study was done for the propranolol enantiomers in the presence of 1-butanol. The intensity changes for propranolol are relatively small upon addition of β-CD in the presence of the butanol alcohol. However, the present work shows that the interaction of (R)-(+)-propranolol with β-CD is influenced by the chirality of 2-butanol in contrast to (S)-(-)-propranolol.This revised version was published online in July 2005 with a corrected issue number.     

Organocatalytic synthesis of quaternary stereocenter bearing a fluorine atom: enantioselective conjugate addition of α-fluoro-β-ketoesters to nitroalkenes

The catalytic enantioselective conjugate addition reaction of α-fluoro-β-ketoesters to nitroalkenes promoted by chiral bifunctional organocatalysts is described. The treatment of α-fluoro-β-ketoesters with nitroalkenes under mild reaction conditions afforded the corresponding Michael adducts containing a fluorinated quaternary stereogenic center with excellent enantioselectivity (up to >99% ee).     

New chiral crown ether stationary phase for the liquid chromatographic resolution of α-amino acid enantiomers

A new chiral stationary phase (CSP) for the liquid chromatographic separation of enantiomers was prepared by bonding a novel enantiopure (diphenyl-substituted 1,1′-binaphthyl) crown ether to 5 μm silica gel. The resulting CSP was applied to the separation of the enantiomers of various natural and unnatural α-amino acids. All α-amino acids tested were resolved very well on the new CSP, with the exception of proline, which does not contain a primary amino group. The resolution of α-amino acid enantiomers on this new CSP was found to be dependent on the type and amounts of organic and acidic modifiers, and on column temperature.     

Introduction of a 7-aza-6-MeO-indoline auxiliary in Lewis-acid/photoredox cooperative catalysis: highly enantioselective aminomethylation of α,β-unsaturated amides

An efficient cooperative chiral Lewis acid/photoredox catalytic system for engaging highly reactive radicals in highly enantioselective conjugate addition to α,β-unsaturated carbonyls is highly desirable. Direct photoexcitation of unbound substrates typically induces undesired background pathways for racemic products and remains a formidable challenge to be addressed in the area of enantioselective photocatalysis. Herein, we report a cooperative catalytic system comprising a chiral Cu(i) complex and an Ir(iii) photocatalyst fueled by visible-light irradiation that allows for seamless integration of the catalytic formation of α-amino alkyl radicals and subsequent enantioselective addition to α,β-unsaturated amides. A 7-aza-6-MeO-indoline attachment on the amide substrates plays a pivotal role in suppressing the undesired pathways, resulting in excellent enantioselectivity and enabling expedited access to valuable γ-aminobutyramides. The indoline amide was readily diversified with full recovery of the azaindoline attachment, highlighting the synthetic utility of this cooperative catalytic system.

An efficient cooperative chiral Lewis acid and photoredox catalytic system towards the highly enantioselective radical conjugate addition of α-amino radicals to α,β-unsaturated amides is developed with the implementation of unique auxiliaries.     

Facile Asymmetric Synthesis of α-Amino Acids Employing Chiral Ligand-Mediated Asymmetric Addition Reactions of Phenyllithium with Imines

A three-step methodology involving an external chiral ligand-mediated asymmetric addition of phenyllithium to an anisidine imine, oxidative removal of N-PMP group, and finally oxidative conversion of the phenyl group to a carboxyl group provides a facile synthesis of optically pure α-amino acid derivatives bearing a bulky α-substituent.     

Asymmetric cleavage of chiral α,β-ethylenic acetals by organolithium reagents

α,β-Ethylenic chiral acetals react regio- and stereoselectively with organolithium reagents. The obtained enol ether may be hydrolyzed into a chiral β-disubstituted aldehyde.     

Practical asymmetric amine nucleophilic approach for the modular construction of protected α-quaternary amino acids

We report the first amine nucleophilic approach for the modular construction of enantioenriched protected α-quaternary amino acids. The key to success is the use of an alcohol solvent, which makes a rationally designed COOMe-bonded Cu-allenylidene electrophilic intermediate stable enough to couple with amine nucleophiles before its decomposition. The reaction features wide functional group tolerance with high enantioselectivity, typically >90% ee, and is amenable to the modification of commercially available bioactive molecules. The resultant protected α-amino acids could be readily converted into a number of precious enantioenriched amines featuring α-hindered tertiary carbon centers, which are otherwise synthetically quite challenging, including those of α-amino aldehyde, peptides or α-vinyl amino ester with >92% ee in excellent yields. This protocol could be utilized for the synthesis of the protected bioactive α-ethylnorvaline in 3 steps, a significant advancement in comparison to an 11-step sequence reported previously.

We report the first amine nucleophilic approach for the modular construction of enantioenriched protected α-quaternary amino acids.     

Asymmetric dihydroxylation of chiral γ-amino α,β-unsaturated esters: Turning the mismatched into the matched case via protective group tuning

Optimal stereoselectivities in the OsO₄-catalyzed dihydroxylation of chiral γ-amino α,β-unsaturated esters are achieved by the proper choice of the protective groups at nitrogen [t-butoxycarbonyl (Boc) versus dibenzyl] and the correct choice of the chiral ligand of the catalyst (AD-mix-α versus AD-mix-β).     

New Nitrogen,Sulfur-, and Selenium-Donating Ligands Derived from Chiral Pyridine Amino Alcohols. Synthesis and Catalytic Activity in Asymmetric Allylic Alkylation

Although many chiral ligands for asymmetric catalysis have been developed, there is still a need for new structures allowing the modular approach. Recently, easy synthesis of chiral pyridine-containing β-amino alcohols has been elaborated by opening respective epoxides with enantiomeric 1-phenylethylamine. This paper reports the synthetic transformation of β-amino alcohols into the new complexing pyridine-containing seleno- and thioethers. The amino alcohols were effectively converted to cyclic sulfonamidates, which were reacted with thiolates or phenyl selenide nucleophile. The reaction was diastereoselective, and its outcome depended on the configuration at the substitution center. The problem was discussed considering DFT optimized structures of both diastereomeric sulfonamidates. New amino-aldimine ligands were also synthesized from chiral pyridine-containing diamines. Nine new chiral ligands were tested in the Tsuji-Trost allylic alkylation resulting in the enantiomerically enriched product in up to 75% ee. The observed stereochemical induction agrees with the prevailing nucleophilic attack at the allylic carbon laying opposite to the complexing nitrogen of pyridine in η³-allylic intermediate complexes.     

A new procedure for the enantioselective vinylogous aldol reaction of Chan’s diene

Chiral δ-hydroxy-β-ketoesters are easily available through the enantioselective vinylogous aldol reaction of Chan’s diene promoted by a SiCl₄/chiral phosphoramide catalytic system. The procedure is conveniently exploited for a very rapid approach to (+)-kavain, a natural bio-active -pyrone compound.     

Asymmetric 1,4-Michael Addition Reaction of Azadienes with α-Thiocyanoindanones Catalyzed by Bifunctional Chiral Squaramide

In this paper, the organocatalytic asymmetric 1,4-Michael addition reaction of azadienes and α-thiocyanoindanones was investigated. A series of chiral benzofuran compounds containing thiocyano group and quaternary carbon center were synthesized in moderate yields with good enantioselectivities (up to 90:10 er) and high diastereoselectivities (up to >95:5 dr). This is the first case of 1,4-Michael addition reaction using α-thiocyanoindanones to obtain a series of chiral thiocyano compounds and further broaden the scope of application of azadiene substrates. In addition, a possible reaction mechanism is also described in the article.