Modified Cyclodextrins as Enantioselective Hosts for Amino Acids

Two modified β‐cyclodextrins, H‐2 and H‐3 , having a flexible appended moiety were studied for the chiral discrimination of the enantiomers of various amino acids by means of fluorescence as signaling option. These hosts quenched the fluorescence intensities of amino acids upon binding. The d‐ enantiomers were better recognized by these hosts. The association constants (K_s) and enantioselectivity factors (α) of the host?guest complexes were calculated.     

Rhodium-Catalyzed Addition of Aryl Boronic Acids to 2,2-Disubstituted Malononitriles

β-Ketonitriles bearing a quaternary carbon at the 2-position were prepared through Rh-catalyzed addition of aryl boronic acids to 2,2-disubstituted malononitriles. In contrast to the previously described transnitrilative cyanation of aryl boronic acids with dialkylmalononitriles, the present reaction avoids retro-Thorpe collapse of the intermediate addition product through the use of a milder base. The reaction was amenable to a variety of aryl boronic acids and disubstituted malononitriles, providing a diverse array of β-ketonitriles. The products could be further derivatized to valuable chiral α,α-disubstituted-β-aminonitriles through addition reactions to the corresponding N-tert-butanesulfinyl imines.     

Chiral α-Amino Acid-Based NMR Solvating Agents

Four new chiral α-(nonafluoro-tert-butoxy)carboxylic acids were synthesized from naturally occurring α-amino acids (alanine, valine, leucine and isoleucine, respectively), and tested in ¹H- and ¹⁹F-NMR experiments as chiral NMR shift reagents. The NMR studies were carried out at room temperature, using CDCl₃ and C₆D₆ as solvents, and (RS)-α-phenylethylamine and (RS)-α-(1-naphthyl)ethylamine as racemic model compounds. To demonstrate the applicability of the reagents, the racemic drugs ketamine and prasugrel were also tested.     

Induction of Asymmetry by Amino Acids

Since the stereoisomers of molecules with one or more asymmetric centers often exhibit different biological activities (e.g. thalidomide, pheromones), stereoselective synthesis as a method of preparative chemistry is rapidly attaining importance. Of the numerous drugs prepared by total synthesis that contain at least one asymmetric center, only about 20% have so far been used in sterically pure form. Amino acids constitute the greatest “chiral pool” of compounds whose enantiomers can be obtained commercially in large amounts; they are gradually being used more and more frequently as auxiliary agents or educts in asymmetric syntheses.     

Catalytic Asymmetric Hydrophosphinylation of 2-Vinylazaarenes to Access P-Chiral 2-Azaaryl-Ethylphosphine Oxides

A chiral Brønsted acid-catalysed asymmetric hydrophosphinylation of 2-vinylazaarenes by secondary phosphine oxides is described. A variety of P-chiral 2-azaaryl-ethylphosphine oxides are synthesized with high yields and ees, of which both the substituents of phosphines and azaarenes can be flexibly modulated, underscoring an exceptionally broad scope of substrates. These adducts are valuable to asymmetric metal catalysis since the resultant P-chiral tertiary phosphines from the reduction of them are verified as a kind of effective C₁-symmetric chiral 1,5-hybrid P,N-ligands. Importantly, this catalysis platform enables the generic and efficient kinetic resolution of P-chiral secondary phosphine oxides. It thus provides an expedient approach to access the enantiomers of the P-chiral tertiary phosphine oxides derived from asymmetric hydrophosphinylation, further improving the utility of the method.     

Total synthesis of PGF2α and 6,15-diketo-PGF1α and formal synthesis of 6-keto-PGF1α via three-component coupling

The asymmetric total synthesis of PGF_2α and 6,15-diketo-PGF_1α and formal synthesis of 6-keto-PGF_1α from a common key intermediate are described. The key intermediate, which has a chiral cyclopentane backbone possessing suitable functional groups with required stereochemistry for both side chains, was prepared from (R)-4-silyloxy-2-cyclopentenone through a three-component coupling reaction. The Wittig reaction, Nozaki-Hiyama-Kishi (NHK) coupling and cross metathesis completed the synthesis of PGF_2α, 6,15-diketo-PGF_1α and 6-keto-PGF_1α.     

Axially Chiral TADF-Active Enantiomers Designed for Efficient Blue Circularly Polarized Electroluminescence

The use of a chiral, emitting skeleton for axially chiral enantiomers showing activity in thermally activated delayed fluorescence (TADF) with circularly polarized electroluminescence (CPEL) is proposed. A pair of chiral stable enantiomers, (−)-(S)-Cz-Ax-CN and (+)-(R)-Cz-Ax-CN, was designed and synthesized. The enantiomers, both exhibiting intramolecular π-conjugated charge transfer (CT) and spatial CT, show TADF activities with a small singlet–triplet energy difference (ΔE_ST) of 0.029 eV and mirror-image circularly polarized luminescence (CPL) activities with large g_lum values. Notably, CP-OLEDs based on the enantiomers feature blue electroluminescence centered at 468 nm with external quantum efficiencies (EQEs) of 12.5 and 12.7 %, and also show intense CPEL with g_EL values of −1.2×10⁻² and +1.4×10⁻², respectively. These are the first CP-OLEDs based on TADF-active enantiomers with efficient blue CPEL.     

Amino Acid Ionic Liquids as Chiral Ligands in Ligand‐Exchange Chiral Separations

Recently, amino acid ionic liquids (AAILs) have attracted much research interest. In this paper, we present the first application of AAILs in chiral separation based on the chiral ligand exchange principle. By using 1‐alkyl‐3‐methylimidazolium L ‐proline (L ‐Pro) as a chiral ligand coordinated with copper(II), four pairs of underivatized amino acid enantiomers—dl ‐phenylalanine (dl ‐Phe), dl ‐histidine (dl ‐His), dl ‐tryptophane (dl ‐Trp), and dl ‐tyrosine (dl ‐Tyr)—were successfully separated in two major chiral separation techniques, HPLC and capillary electrophoresis (CE), with higher enantioselectivity than conventionally used amino acid ligands (resolution (R_s)=3.26–10.81 for HPLC; R_s=1.34–4.27 for CE). Interestingly, increasing the alkyl chain length of the AAIL cation remarkably enhanced the enantioselectivity. It was inferred that the alkylmethylimidazolium cations and L ‐Pro form ion pairs on the surface of the stationary phase or on the inner surface of the capillary. The ternary copper complexes with L ‐Pro are consequently attached to the support surface, thus inducing an ion‐exchange type of retention for the dl ‐enantiomers. Therefore, the AAIL cation plays an essential role in the separation. This work demonstrates that AAILs are good alternatives to conventional amino acid ligands for ligand‐exchange‐based chiral separation. It also reveals the tremendous application potential of this new type of task‐specific ILs.     

Enantiomeric separation of glycidyl tosylate by CE: Application to the study of catalytic asymmetric epoxidation of allyl alcohol

A CE method using CDs as chiral selectors was developed and validated to achieve the separation of glycidyl tosylate enantiomers originated by in situ derivatization of glycidol enantiomers obtained in asymmetric epoxidation of allyl alcohol with chiral titanium‐tartrate complexes as catalysts. The effects of the nature, pH and concentration of the buffer, the nature and concentration of chiral selector, the addition of SDS, methanol, ethanol or 2‐propanol, the capillary temperature, the effective capillary length and the applied voltage on the chiral resolution of glycidyl tosylate enantiomers were investigated. The best separation conditions were achieved using a Tris‐borate buffer mixture (50 and 25 mM, respectively) at pH=9.3 with a dual CD system consisting of 2.5% succinyl‐β‐CD and 1.0% β‐CD w/v at 15°C. A baseline separation (resolution～2.0) of the glycidyl tosylate enantiomers was obtained in a relatively short time (less than 12 min). Satisfactory results were obtained in terms of linearity (r>0.99) and intermediate precision (RSD below 8.5%). The LOD and LOQ were 3.0 and 10.0 mg/L, respectively, and the recoveries ranged from 99.8 to 108.8%. Finally, the method was applied to the determination of the enantiomeric excess and the yield obtained in the asymmetric epoxidation of allyl alcohol employing chiral titanium‐tartrate complexes as catalysts after an in situ derivatization of glycidol enantiomers to glycidyl tosylate.     

One Stone for Three Birds‐Rhodium‐Catalyzed Highly Diastereoselective Intramolecular [4+2] Cycloaddition of Optically Active Allene‐1,3‐dienes

RhCl(PPh₃)₃‐catalyzed [4+2] intramolecular cycloaddition of optically active axially chiral allene‐dienes afforded cis‐fused [3.4.0]‐bicyclic products with three chiral centers in good yields with an excellent chemo‐ and diastereoselectivity. A pair of enantiomers of such products was generated highly selectively from both enantiomers of starting allene‐dienes, indicating that the axial chirality dictated the absolute configurations of the three in situ generated chiral centers with a very high efficiency of chirality transfer.     

Axially Chiral TADF‐Active Enantiomers Designed for Efficient Blue Circularly Polarized Electroluminescence

The use of a chiral, emitting skeleton for axially chiral enantiomers showing activity in thermally activated delayed fluorescence (TADF) with circularly polarized electroluminescence (CPEL) is proposed. A pair of chiral stable enantiomers, (?)‐(S)‐Cz‐Ax‐CN and (+)‐(R)‐Cz‐Ax‐CN, was designed and synthesized. The enantiomers, both exhibiting intramolecular π‐conjugated charge transfer (CT) and spatial CT, show TADF activities with a small singlet–triplet energy difference (ΔE_ST) of 0.029 eV and mirror‐image circularly polarized luminescence (CPL) activities with large g_lum values. Notably, CP‐OLEDs based on the enantiomers feature blue electroluminescence centered at 468 nm with external quantum efficiencies (EQEs) of 12.5 and 12.7 %, and also show intense CPEL with g_EL values of ?1.2×10^?2 and +1.4×10^?2, respectively. These are the first CP‐OLEDs based on TADF‐active enantiomers with efficient blue CPEL.     

Organocatalytic enantioselective sulfa-Michael addition of thiocarboxylic acids to β-trifluoromethyl-α,β-unsaturated ketones for the construction of stereogenic carbon center bearing a sulfur atom and a trifluoromethyl group

An organocatalyzed asymmetric sulfa-Michael addition of thiocarboxylic acids to β-trifluoromethyl-α,β-unsaturated ketones with a chiral bifunctional amine-squaramide as the catalyst is presented. A wide range of chiral ketone compounds bearing a sulfur atom and a trifluoromethyl group at the stereogenic carbon center could be obtained with excellent results (up to 99% yield, 97% ee) under mild conditions. The developed catalytic system is well-tolerated to both (E)-and (Z)-β-trifluoromethylated-α,β-unsaturated ketones.     

Editorial

Abstract

Asymmetric syntheses of optically active polymethacrylate, polyacrylate, polyacrylamide, and polyisocyanate with helical conformation and their chiral recognition abilities are described. 1-Phenyldibenzosuberyl methacrylate (PDBSMA) gave a purely onehanded-helical, optically active polymer ([α]₃₆₅ +1670 ～ +1780º) with almost perfectly isotactic structure by anionic polymerization using optically active initiators. Radical polymerizations of PDBSMA using chiral initiators, chain transfer agents, and additives also afforded optically active polymers with a prevailing onehanded helicity. Triphenylmethyl acrylate yielded an optically active, helical polymer ([α]₃₆₅ +102º) having a dyad isotacticity of 70% using an optically active anionic initiator. Although the polyacrylate demonstrated chiral recognition ability as a chiral stationary phase for HPLC, the ability was low mainly because of the low degree of one-handedness. N-(3-Chlorophenyl)-N-phenylacrylamide gave an optically active, helical polymer ([α]_365–343º) in the asymmetric anionic polymerization; the polymer had a dyad tacticity of 77%. Optically active polyisocyanates with a predominantly one-handed helical conformation were prepared in homo-and co-polymerization of optically active phenyl isocyanate derivative. These polyisocyanates showed the ability to discriminate enantiomers in solution.     

Asymmetric N-Alkylation of 1H-Indoles via Carbene Insertion Reaction

An intermolecular enantioselective N-alkylation reaction of 1H-indoles has been developed by cooperative rhodium and chiral phosphoric acid catalyzed N−H bond insertion reaction. N-Alkyl indoles with newly formed stereocenter adjacent to the indole nitrogen atom are produced in good yields (up to 95 %) with excellent enantioselectivities (up to >99 % ee). Importantly, both α-aryl and α-alkyl diazoacetates are tolerated, which is extremely rare in asymmetric X−H (X=N, O, S et al.) and C−H insertion reactions. With this method, only 0.1 mol % of rhodium catalyst and 2.5 mol % of chiral phosphoric acid are required to complete the conversion as well as achieve the high enantioselectivity. Computational studies reveal the cooperative relay of rhodium and chiral phosphoric acid, and the origin of the chemo and stereoselectivity.     

Preparation and Characterization of New C2‐ and C1‐Symmetric Nitrogen,Oxygen, Phosphorous,and Sulfur Derivatives and Analogs of TADDOL. Part III

A brief overview is presented of the field of organocatalysis using chiral H‐bond donors, chiral Brønsted acids, and chiral counter‐anions (Fig. 1). The role of TADDOLs (=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanols) as H‐bond donors and the importance of an intramolecular H‐bond for acidity enhancement are discussed. Crystal structures of TADDOLs and of their N‐, S‐, and P‐analogs (Figs. 2 and 3) point the way to proposals of mechanistic models for the action of TADDOLs as organocatalysts (Scheme 1). Simple experimental two‐step procedures for the preparation of the hitherto strongest known TADDOL‐derived acids, the bicyclic phosphoric acids ( 2 in Scheme 2) and of a phosphoric‐trifluorosulfonic imide ( 9 in Scheme 4), are disclosed. The mechanism of sulfinamide formation in reactions of TADDAMIN with trifluoro‐sulfonylating reagents is discussed (Scheme 3). pK_a Measurements of TADDOLs and analogs in DMSO (reported in the literature; Fig. 5) and in MeO(CH₂)₂OH/H₂O (described herein; Fig. 6) provide information about further possible applications of this type of compounds as strong chiral Brønsted acids in organocatalysis.     

Quantification of salsolinol enantiomers by stable isotope dilution liquid chromatography with tandem mass spectrometric detection

Salsolinol, 1‐methyl‐6,7‐dihydroxy‐2,3,4,5‐tetrahydroisoquinoline (SAL), is a precursor of a Parkinsonian neurotoxin, N‐methysalsolinol (N‐methyl‐SAL). Previous studies have shown that individual enantiomers of N‐methyl‐SAL possess distinct neurotoxicological properties. In this work, a chiral high‐performance liquid chromatography (HPLC) method with electrospray ionization tandem mass spectrometric (ESI‐MS/MS) detection was developed for the quantification of (R/S)‐SAL enantiomers. Enantioseparation was achieved on a β‐cyclodextrin‐bonded silica gel column, and the resolved enantiomers were detected by ESI‐MS/MS operated in positive ion mode. The ESI collision‐induced dissociation (CID) mass spectrum of SAL was studied together with that of its deuterium‐labeled analog (i.e. salsolinol‐α,α,α,1‐d₄, SAL‐d₄) so that the fragmentation pathways could be elucidated. Further, using SAL‐d₄ as internal standard in HPLC/MS/MS analysis of SAL improved significantly assay accuracy and reliability. Determination of (R/S)‐SAL enantiomers present in food samples such as dried banana chips was demonstrated. Copyright © 2008 John Wiley & Sons, Ltd.     

Catalytic Asymmetric Allenylation: Regulation of the Equilibrium between Propargyl- and Allenylstannanes during the Catalytic Process

Achiral substrates 1 and 2 can be regioselectively converted into chiral allenyl alcohols 3 through the title reaction [Eq. (1)] with the synergetic reagent iPrSBEt₂ and a chiral Ti^IV catalyst. The dramatic regioselectivity originates from the regulation of the equilibrium between propargyl- and allenylstannanes during the catalytic process.     

Synthesis of (+)- and (−)-Tetrabenazine from the Resolution of α-Dihydrotetrabenazine

Abstract

Tetrabenazine (1) was reduced with NaBH₄ to α-dihydrotetrabenazine (2) and then resolved with di-p-toluoyl-L-tartrate and di-p-toluoyl-D-tartrate to subsequently give (+)- and (?)-α-dihydrotetrabenazine. The enantiomers were oxidized under Swern conditions to prepare samples of (+)-tetrabenazine and (?)-tetrabenazine. The samples were optically pure by chiral HPLC analysis.     

Asymmetric synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivatives

The use of several chiral trifluoromethylated building blocks 1a, 1b, 9a and 9b was attempted to synthesize of syn-(3-trifluoromethyl)cysteine. A novel and efficient enantioselective synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivatives 12a and 12b was successfully achieved.     

trans-[RuCl2(phosphane)2(1,2-diamine)] and Chiral trans-[RuCl2(diphosphane)(1,2-diamine)]: Shelf-Stable Precatalysts for the Rapid,Productive, and Stereoselective Hydrogenation of Ketones

A turnover number (TON) of 2 400 000 and a turnover frequency (TOF) of 63 s⁻¹ are achieved with the chiral Ru^II complex 1 (R=p-CH₃C₆H₄) in the asymmetric hydrogenation of acetophenone. Carbonyl-selective asymmetric hydrogenation of α,β-unsaturated ketones proceeds in the presence of these Ru^II catalysts, and 4-substituted cyclohexanones are selectively converted into cis alcohols.