Molecular modeling of salt (lithium chloride) effects on the enantioselectivity of diethylzinc addition to benzaldehyde in the presence of chiral beta-amino alcohols

Beta-amino alcohols (S,S,S)-1 and (R,R,S)-1, derived from cyclohexene oxide and containing alpha-phenylethyl auxiliaries, were examined as chiral promoters in the addition of diethylzinc to benzaldehyde. In agreement with literature precedent, the N-alpha-phenylethyl chiral auxiliary had no significant impact on enantioinduction, which is determined by the configuration of the framework's C(OH), with unlike induction. Contrary to some literature reports, stereoinduction by lithium salt derivatives of (S,S,S)-1 and (R,R,S)-1 was lower than that obtained with the free amino alcohol. Remarkable lithium chloride salt effects were observed in the reaction. In particular, an opposite chiral induction was found with (S,S,S)-1-Li(2) as ligand and in the presence of "inert" salt. N-Alkylated derivatives (S,S,S)-3-7 proved to be more efficient ligands, providing higher yields and enantioselectivities in the formation of carbinols (R)- or (S)-2. BP86/DN**//PM3 theoretical calculations proved remarkably successful in reproducing the experimental observations and permitted expansion of Noyori's catalytic cycle [J. Am. Chem. Soc. 1995, 117, 6327] to understand the relevant N-substitution and medium salt effects that determine the enantioselection in this catalytic asymmetric reaction.     

Rhodium complexes with chiral counterions: achiral catalysts in chiral matrices

The neutral complexes [Rh(I)(NBD)((1S)-10-camphorsulfonate)] (2) and [Rh(I)((R)-N-acetylphenylalanate)] (4) reacted with bis-(diphenylphosphino)ethane (dppe) to form the cationic Rh(I)(NBD)(dppe) complexes, 5 and 6, respectively, accompanied by their corresponding chiral counteranions. Analogously, 4 reacted with 4,4^′-dimethylbipyridine to yield complex 7. Complexes 5 and 6 disproportionated in aprotic solvents to form the corresponding bis-diphosphine complexes 8 and 9, respectively. 8 was characterized by an X-ray crystal structure analysis. In order to form achiral Rh(I) complexes bearing chiral countercations new sulfonated monophosphines 13-16 with chiral ammonium cations were synthesized. Tris-triphenylphosphinosulfonic acid (H₃TPPS, 11) was used to protonate chiral amines to yield chiral ammonium phosphines 14-16. Thallium-tris-triphenylphosphinosulfonate (Tl₃TPPS, 12) underwent metathesis with a chiral quartenary ammonium iodide to yield the proton free chiral ammonium phosphine 13. Phosphines 15 and 16 reacted with [Rh(NBD)₂]BF₄ to afford the highly charged chiral zwitterionic complexes [Rh(NBD)(TPPS)₂][(R)-N,N-dimethyl-1-(naphtyl)ethylammonium]₅ (17) and [Rh(NBD)(TPPS)₂][BF₄][(R)-N,N-dimethyl-phenethylammonium]₆ (18), respectively. Complexes 5, 6, and 18 were tested as precatalysts for the hydrogenation of de-hydro-N-acetylphenylalanine (19) and methyl-(Z)-(α)-acetoamidocinnamate (MAC, 20) under homogeneous and heterogeneous (silica-supported and self-supported) conditions. None of the reactions was enantioselective.     

Solution study of chiral 1,2-diol Yb chelates through near-IR circular dichroism

Ytterbium is efficiently chelated by 1,2-diols in a variety of very different solvents. We found a set of solution equilibria among three complexes of minimum formula [Yb·(diol)], [Yb·(diol)₂] and [Yb·(diol)₃]. By extensive near-Infrared circular dichroism (NIR CD) investigation, we determined fingerprint CD spectra of the di- and tri-chelated species and the relative formation constants. Since NIR CD is sensitive only to chiral Yb-species, NIR CD can be very useful for studying complex mixtures, such as those used in enantioselective catalysis and involving a chiral non-racemic diol as an auxiliary and an ytterbium salt. The chiroptical spectra show completely conserved features through very different diol structures, demonstrating the identity of the coordination polyhedron around Yb(III) and giving rise to a new empirical method for assigning 1,2-diols absolute configuration.     

Synthesis of chiral crown ethers and complexation with chiral protonated amine compounds: X-ray crystal and nuclear magnetic resonance studies of perchlorate salt of chiral benzo-monoaza-15-crown-5 and chiral monoaza-15-crown-5

The X-ray crystal structure of IX, perchlorate salt of R-(?-2-ethyl-N-benzyl-4,7,19,13-tetraoxa-8,9-benzo-1-azacyclopentadec-8-ene has been determined. In the molecule, the protonated nitrogen atom participates in two N-H?O hydrogen bonds. The unusually high proton affinity of aza crown ether leads to the formation of diastreomer instead of complex formation with chiral R-(+)-1-phenyl ethyl ammonium perchlorate and S-(?)-1-phenyl ethyl ammonium perchlorate. The complex ability of host ethers was evaluated in terms of structural modification.     

Novel C2-symmetric chiral 18-crown-6 derivatives with two aromatic sidearms as chiral NMR discriminating agents

Novel C₂-symmetric chiral 18-crown-6 derivatives with two aromatic sidearms 2-4 were prepared, and their enantiomeric recognition abilities as chiral NMR discriminating agents towards primary ammonium salts were examined. Among these chiral crown ethers, the most effective enantiomeric discrimination of racemic ammonium salts in the ¹H NMR spectra was attained by the derivative with two pyrenylmethyl sidearms.     

Asymmetric intermolecular C-H functionalization of benzyl silyl ethers mediated by chiral auxiliary-based aryldiazoacetates and chiral dirhodium catalysts

[reaction: see text] C-H functionalization of benzyl silyl ethers by means of rhodium-catalyzed insertions of aryldiazoacetates can be achieved in a highly diastereoselective and enantioselective manner by judicious choice of chiral catalyst or auxiliary. The dirhodium tetraprolinates such as Rh2((S)-DOSP)4 have been widely successful as chiral catalysts in the C-H functionalization chemistry of aryldiazoacetates, but give poor enantioselectivity in the reactions of aryldiazoacetates with benzyl silyl ether derivatives. The use of (S)-lactate as a chiral auxiliary resulted in C-H functionalization with moderately high diastereoselectivity (79-88% de) and enantioselectivity (68-85% ee). The best results (91-95% de, 95-98% ee), however, were achieved using Hashimoto's Rh2((S)-PTTL)4 catalyst.     

Efficient synthesis of a chiral [4]pseudocatenane and its derivatives: a novel ship's wheel-like interlocked structure

A novel chiral[4]pseudocatenane 5H(3)[PF(6)](3) was synthesized efficiently by treatment of a solution of chiral triptycene-based tri(crown ether) 1 and three equivalents of a bis[p-(but-3-enyloxy)benzyl]ammonium salt in CH(2)Cl(2) with a Grubbs II catalyst, followed by hydrogenation. It was found that the ammonium groups in 5H(3)[PF(6)](3) could be deprotonated by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile or dimethyl sulfoxide (DMSO). Consequently, N-acylation of the ammonium groups was easily performed in the presence of DBU, which resulted in a new class of neutral highly ordered interlocked molecules in good yields. In particular, the incorporation of stopper units, for example, diethyl phosphoramidate, lead to the isolation of the interlocked molecule 10 with an interesting ship's wheel-like structure, which was structurally studied with the help of detailed NMR experiments. Compared with 1, it was further found that the Cotton effect of (R)-1,1'-binaphthyl chromophore at 241 nm was greatly reduced in 5H(3)[PF(6)](3) and its derivatives. Moreover, a new positive Cotton effect at 248 nm appeared in the interlocked molecules; this observation could be attributed to the chirality transfer from the binaphthyl units to the macrocycles lying in the cavities of 1.     

Facile synthesis and optical resolution of inherently chiral fluorescent calix[4]crowns: enantioselective recognition towards chiral leucinol

A series of tri-O-alkylated inherently chiral fluorescent calix[4]crowns in the cone conformations and a series of tetra-O-alkylated inherently chiral fluorescent calix[4]crowns in the partial cone conformations have been synthesized. By condensing with chiral auxiliary (S)-BINOL, the resulting diastereomers could be separated via preparative TLC. We found that the size of the crown moiety effected the separation of the diastereomers. Further, removal of the BINOL unit by hydrolysis furnished pairs of enantiomers with optical purity. Moreover, we found that a tetra-O-alkylated inherently chiral fluorescent calix[4]crown-6 in the partial cone conformation 6c showed considerable enantioselective recognition capability towards chiral leucinol.     

Enantiomeric recognition and separation of chiral organic ammonium salts by chiral pyridino-18-crown-6 ligands

Abstract

Optically pure allyloxy and dimethyl-substituted pyridino-18-crown-6 (8) was attached to silica gel by the following reactions. 4-Allyloxy-2,6-pyridinedimethyl ditosylate (23) was first prepared from chelidamic acid. Ditosylate 23 was treated with (S,S)-dimethyl-substituted tetraethylene glycol to form 8. Ligand 8 was treated with triethoxysilane using a platinum catalyst. The resulting chiral crown-substituted triethoxysilane 32 was reacted with silica gel in toluene at 90 C to attach the crown to silica gel. Preliminary results of the separation of [α-(1-naphthyl)ethyl]ammonium perchlorate into its (R) and (S) forms using the bound chiral crown with acetone/methanol (7/3) (v/v) as the eluant are reported. The preparation of chiral dimethyl(allyloxyphenyl)pyridino-18-crown-6 (9) that could be attached to silica gel on the side opposite to the pyridine ring is also reported.     

Reversed-phase chiral HPLC and LC/MS analysis with tris(chloromethylphenylcarbamate) derivatives of cellulose and amylose as chiral stationary phases

Three polysaccharide-derived chiral stationary phases (CSP) were evaluated for the resolution of more than 200 racemic compounds of pharmaceutical interest in the reversed-phase (RP) separation mode. The population of test probes was carefully evaluated in order to insure that it covers as completely as possible all structural diversity of chiral pharmaceuticals. RP showed the highest potential for successful chiral resolution in HPLC and LC/MS analysis when compared to normal phase and polar organic separation modes. Method development consisted of optimizing mobile phase eluting strength, nature of organic modifier, nature of additive and column temperature. The newer CSPs, cellulose tris(3-chloro-4-methylphenylcarbamate) and amylose tris(2-chloro-5-methylphenylcarbamate), were compared to the commonly used cellulose tris(3,5-dimethylphenylcarbamate) in regards to their ability to provide baseline resolution. Comparable success rates were observed for these three CSPs of quite complimentary chiral recognition ability. The same method development strategy was evaluated for LC/MS analysis. Diethylamine as additive had a negative effect on analyte response with positive ion mode electrospray (ESI⁺) MS(/MS) detection, even at very low concentration levels (e.g., 0.025%). Decreasing the organic modifier (acetonitrile or methanol) content in the mobile phase often improved enantioselectivity. The column temperature had only a limited effect on chiral resolution, and this effect was compound dependent. Ammonium hydrogencarbonate was the preferred buffer salt for chiral LC with ESI⁺ MS detection for the successful separation and detection of most basic pharmaceutical racemic compounds. Ammonium acetate is a viable alternative to ammonium hydrogencarbonate. Aqueous formic acid with acetonitrile or methanol can be successfully used in the separation of acidic and neutral racemates. Cellulose tris(3-chloro-4-methylphenylcarbamate) and amylose tris(2-chloro-5-methylphenylcarbamate) emerge as CSPs of wide applicability in either commonly used separation modes rivaling such well established CSPs as cellulose tris(3,5-dimethylphenylcarbamate). Screening protocols including these two new CSPs in the preferentially screened set of chiral columns have higher success rates in achieving baseline resolution in shorter screening time.     

Asymmetric synthesis of beta-hydroxy amino acids via aldol reactions catalyzed by chiral ammonium salts

The Cinchona alkaloid derived chiral ammonium salt developed by Park and Jew functions as an effective catalyst for the synthesis of beta-hydroxy alpha-amino acids via asymmetric aldol reactions under homogeneous conditions. The syn diastereomers are obtained in good ee, and aryl-substituted aliphatic aldehydes are the best substrates for the reaction. These results represent the highest ee's obtained to date in direct aldol reactions of glycine equivalents catalyzed by inexpensive, readily prepared chiral ammonium salts.     

Chiral alpha-substituted carbonyls and alcohols from the S(N)2' displacement of cuprates on chiral carbonates: An alternative to the alkylation of chiral enolates

A highly stereoselective sequence of reactions, based on the anti-selective S(N)2' addition of cuprates to allylic carbonates, transforms alkynes or alkenyl halides into carbonyls having alpha-chiral centers. The method, which uses menthone as a chiral auxiliary, is a useful alternative to the alkylation of chiral enolates with the added advantage of allowing for the "alkylation" of sec- and tert-alkyl and aryl groups.     

Rhodium-catalyzed diastereoselective 1,2-addition of arylboronic acids to chiral trifluoroethyl imine

Rhodium-catalyzed 1,2-addition of arylboronic acids 4a-j to chiral trifluoroethyl imine 3 afforded diastereomerically enriched sulfinamides 5a-j. The chiral auxiliary of the sulfinamide products was readily removed under acidic methanolysis to provide the corresponding trifluoroethylamine analogs 6a-j.     

Stereoselective electrochemical carboxylation: 2-phenylsuccinates from chiral cinnamic acid derivatives

Chiral 2-phenyl succinic ester derivatives have been obtained under mild conditions, in short times and with satisfactory yields by electrochemical reduction of chiral cinnamic acid derivatives under a CO2 atmosphere. When 4R-(diphenylmethyl)-oxazolidin-2-one was used as a chiral auxiliary the two diastereoisomers could be easily separated by flash chromatography and the R-isomer was obtained as major product.     

Pd-catalyzed asymmetric allylic alkylation of glycine imino ester using a chiral phase-transfer catalyst

Pd-catalyzed asymmetric allylic alkylation of the glycine imino ester 1a has been developed using a chiral quaternary ammonium salt 3d without chiral phosphine ligands. The proper choice of the achiral Pd ligand, P(OPh)3, is important to achieve high enantioselectivity. By this method with the dual catalysts, numerous enantiomerically enriched alpha-allylic amino acids 4a-h could be prepared with comparable to higher enantioselectivity than that of the conventional asymmetric alkylation of 1a. In addition, the Pd-catalyzed reaction of 1a with 1-phenyl-2-propenyl acetate 2i afforded the branch product 6 with high enantio- and diastereoselectivity (>95% de, 85% ee).     

Selective synthesis of either enantiomer of alpha-amino acids by switching the regiochemistry of the tricyclic iminolactones prepared from a single chiral source

Preparation of l-alpha-amino acids was easily accomplished simply by exchanging the position of the lactone group of our recently reported chiral template 1 from C2 to C3. The new chiral template 7 was prepared in 54% overall yield over five steps from (1R)-(+)-camphor. Alkylation of iminolactone 7 afforded the alpha-monosubstituted products in good yields and excellent diastereoselectivities (>98%). Hydrolysis of the alkylated iminolactones furnished the desired l-alpha-amino acids in good yields and ee with nearly quantitative recovery of chiral auxiliary 4.     

(S)-O-acetyllactyl chloride – a versatile chiral auxiliary in stereodifferentiation of enantiomeric flavor components

The stereodifferentiation of chiral secondary alcohols, 4(5)-alkyl-substituted γ (δ)-lactones via corresponding 1, 4(1, 5)-diols, chiral 1, 3-diols, and 1-thioalkan-3-ols was carried out by diastereomeric derivatization with (S)-O-acetyllactyl chloride as a chiral auxiliary. This procedure is a convenient and reliable method for screening the enantiomeric composition of these naturally occurring flavor volatiles.     

Design of N-spiro C2-symmetric chiral quaternary ammonium bromides as novel chiral phase-transfer catalysts: synthesis and application to practical asymmetric synthesis of alpha-amino acids

A series of C(2)-symmetric chiral quaternary ammonium bromides 10 and 11 have been designed as a new, purely synthetic chiral phase-transfer catalyst, and readily prepared from commercially available optically pure 1,1'-bi-2-naphthol as a basic chiral unit. The details of the synthetic procedures of each requisite chiral binaphthyl subunit have been disclosed, and the structures of the assembled N-spiro chiral quaternary ammonium bromides 11a and 11f were unequivocally determined by single-crystal X-ray diffraction analysis. The reactivity and selectivity of these chiral ammonium bromides as chiral phase-transfer catalysts have been evaluated in the asymmetric alkylation of the benzophenone Schiff base of glycine ester 7 under mild liquid-liquid phase-transfer conditions, and the optimization of the reaction variables (solvent, base, and temperature) has also been conducted. Further, the scope and limitations of this asymmetric alkylation have been thoroughly investigated with a variety of alkyl halides, in which the advantage of the unique N-spiro structure of 11 and dramatic effect of the steric as well as the electronic properties of the aromatic substituents on the 3,3'-position of one binaphthyl moiety have been particularly emphasized. Finally, the potential synthetic utility of the present method for the practical asymmetric synthesis of structurally diverse natural and unnatural alpha-amino acids has been demonstrated by its successful application to the facile asymmetric syntheses of (S)-N-acetylindoline-2-carboxylate, a key intermediate in the synthesis of the ACE inhibitor, and l-Dopa (l-3,4-dihydroxyphenylalanine) ester and its analogue.     

Synthesis and stereochemical properties of chiral square complexes of iron(II)

The hexadentate, and ditopic ligand 2,5-bis([2,2']bipyridin-6-yl)pyrazine yields a chiral, tetrameric, square-shaped, self-assembled species upon complexation with Fe2+ ions. The racemate of this complex was resolved with antimonyl tatrate as the chiral auxiliary. The purity of the enantiomer was determined by NMR spectroscopy, by using a chiral, diamagnetic shift reagent, and by circular dichroism (CD). The CD spectrum was also calculated by time-dependent density functional theory, and the correlation that was found between CD spectrum and configuration was confirmed by X-ray cristallography. When a "chiralised" version of the ligand was used instead, the corresponding iron complex was obtained in diastereomerically pure form.     

Highly enantioselective radical addition to N-benzoyl hydrazones using chiral ammonium salts

In the presence of a protonated cinchonine derivative, radical addition reactions proceeded efficiently, affording addition adducts in high yields with an extremely high enantioselectivity. The chiral ammonium salt was recyclable after a simple aqueous workup. The reaction provides environmentally benign reaction conditions.