Synthesis of C1-symmetric chiral tripodal oxazolines through an oxazoline exchange reaction with amino alcohols

Various C₁-symmetric chiral tripodal tris(oxazolines) with two different oxazoline units were synthesized from chiral C₃-symmetric tris(oxazolines) through an oxazoline exchange reaction with amino alcohols in the presence of zinc chloride. Evaluation of the new oxazolines as chiral molecular receptor showed that some of the receptors have chiral discrimination ability.     

Synthetic studies of the HIV-1 protease inhibitive didemnaketals: precise and stereocontrolled synthesis of the key mother spiroketal

The precise and stereocontrolled synthesis of the C₉-C₂₃ portion, the key mother spiroketal of the HIV-1 protease inhibitive didemnaketals from the ascidian Didemnum sp., has been carried out through multisteps starting from (R)-pulegone as the chiral template. This approach involved the distereoselective construction of eight chiral centers by intramolecular chiral inducement and the coupling of two fragments by Julia reaction.     

Chiral solvating agents for carboxylic acids based on the salen moiety

A series of chiral salen C₂-symmetric aminophenols 1–4, which were derived from (1R,2R)- or (1S,2S)-1,2-diphenylethane-1,2-diamine with the corresponding salicylic aldehyde through a [2+2] condensation reaction, have been prepared. The NMR studies demonstrated that they can function as chiral solvating agents for the determination of the enantiomeric purity of chiral carboxylic acids.     

Development of a new class of C1-symmetric bisphosphine ligands for rhodium-catalyzed asymmetric hydrogenation

A new class of C₁-symmetric bisphosphine ligands with three hindered quadrants have been obtained through facile synthesis from chiral BINOL derivatives. Their rhodium complexes have exhibited high enantioselectivities (up to 98% ee) in the asymmetric hydrogenation of various unsaturated prochiral olefins, providing an efficient catalytic system for the enantioselective synthesis of chiral amino acids and amines.     

Development of a chiral host system tunable via changes in a 21-column packing structure

A tunable chiral host system was developed by the self-assembly of a chiral 2₁-column structure formed from (1R,2R)-1,2-diphenylethylenediamine and dicarboxylic acid. This host system can include guest molecules by changing the packing of a chiral 2₁-column enantioselectively.     

Stereoselective total synthesis of almorexant

A highly stereoselective synthesis of almorexant has been achieved using (R)-tert-butanesulfinamide as a chiral source. The chiral tetrahydroisoquinoline core was constructed through allylation of chiral N-sulfinyl imine followed by ring closure of the secondary amide with a tethered halide. The chiral α-phenyl amide was introduced by means of S_N2 substitution of (S)-methyl 2-phenyl-2-(tosyloxy)acetate with chiral tetrahydroisoquinoline.     

Palladium asymmetric reduction of β-carboline imines mediated by chiral auxiliaries assisted by microwave irradiation

An alternative synthetic approach for the introduction of chirality in β-carboline moiety through in situ reduction of N-acyliminium ion intermediates generated from imine 2 and chloroformate of 8-phenylmenthyl as chiral auxiliary was achieved. The method applied microwave-assisted irradiation and used PdCl₂/Et₃SiH protocol as a mild reducing agent, which decreased reaction times to minutes when compared to the conventional thermal reactions. The diastereoselectivity (4-12:1) of the reduction produced R-amines, which were assigned after chiral auxiliary removal and spectroscopic data compared to products obtained from Noyori asymmetric hydrogenation catalyst.     

Tandem enantioselective conjugate addition-Mannich reactions: efficient multicomponent assembly of dialkylzincs, cyclic enones and chiral N-sulfinimines

A convenient access to enantiopure β-amino ketones through a multicomponent reaction of dialkyl zinc reagents, cyclic enones and chiral N-tert-butanesulfinimines is disclosed. Four diastereoisomers can be selectively obtained by the appropriate choice of the chiral ligand (L or ent-L) and the chiral N-sulfinimine (R_S or S_S). The protocol is particularly efficient when enolisable N-sulfinimines are used.     

New C2-symmetric chiral phosphinite ligands based on amino alcohol scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones

Asymmetric transfer hydrogenation processes of ketones with chiral molecular catalysts are attracting increasing interest from synthetic chemists due to their operational simplicity. C₂-symmetric catalysts have also received much attention and been used in many reactions. A series of new chiral C₂-symmetric bis(phosphinite) ligands has been prepared from corresponding amino acid derivated amino alcohols or (R)-2-amino-1-butanol through a three- or four-step procedure. Their structures have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis. ¹H-³¹P NMR, DEPT, ¹H-¹³C HETCOR or ¹H-¹H COSY correlation experiments were used to confirm the spectral assignments. In situ prepared ruthenium catalytic systems were successfully applied to ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives by iso-PrOH. Under optimized conditions, these chiral ruthenium catalyst systems serve as catalyst precursors for the asymmetric transfer hydrogenation of acetophenone derivatives in iso-PrOH and act as good catalysts, giving the corresponding optical secondary alcohols in 99% yield and up to 79% ee.     

Enantiodivergent formation of a chiral cytosine crystal by removal of crystal water from an achiral monohydrate crystal under reduced pressure

An achiral nucleobase cytosine forms an achiral monohydrate crystal (space group: P2₁/c) by crystallization from a water solution. It was found that the removal of crystal water under reduced pressure at room temperature afforded a chiral crystal of anhydrous cytosine (P2₁2₁2₁). The crystal chirality of anhydrous cytosine corresponds to the enantiotopic crystal face of the achiral monohydrate; therefore, when the enantiotopic b¹-face is exposed to the reduced pressure, dehydration occurred in the direction from the b¹-face to provide [CD(+)310_KBr]-cytosine crystal. In contrast, dehydration from the b²-face gave the opposite enantiomorphous [CD(?)310_KBr]-cytosine crystal. The correlation between enantiotopic faces and the formed crystal chirality is opposite to that from dehydration by heating. The formed chiral cytosine crystals act as a chiral trigger for asymmetric autocatalysis with enantioenrichment amplification of pyrimidylalkanol.     

Synthesis and structures of two novel non-centrosymmetric metal-organic polymers containing 2-(pyridin-4-yl)-1H-imidazole-4,5-dicarboxylic acid ligands

Two novel non-centrosymmetric coordination polymer, [Zn₂(PIDC)(H₂O)Cl]_n (1) and {[Mn(HPIDC)H₂O]·2H₂O}_n (2) have been synthesized through hydrothermal method and characterized by IR, elemental analysis and single-crystal X-ray diffraction. Complex 1 crystallized in a chiral space group P2₁2₁2₁ has a 2D network structure. Complex 2 is a 3D open framework with 1D channel where 1D zigzag water chains are reside through hydrogen-bonding interactions and crystallized in a chiral space group C_c. Both 1 and 2 display a strong second harmonic generation (SHG) response.     

An enantiopure galactose oxidase model: synthesis of chiral amino alcohols through oxidative kinetic resolution catalyzed by a chiral copper complex

An enantiopure galactose oxidase (GO) enzyme model has been synthesized from readily available (R)-BINAM and Cu(OTf)₂, and the enantiopure GO model has been effectively used in situ as an efficient chiral catalyst for the synthesis of chiral amino alcohols through oxidative kinetic resolution (OKR), where molecular oxygen is used as the sole oxidant. Under the proposed catalytic conditions, both ortho- and para-substituted amino alcohols were resolved with good to excellent enantiomeric excesses through oxidative kinetic resolution.     

Univocal syntheses of 2- and 3-hydroxymethyl-2,3-dihydro[1,4]dioxino[2,3-b]pyridine enantiomers

The enantiomers of 2- and 3-hydroxymethyl substituted 2,3-dihydro[1,4]dioxino[2,3-b]pyridine 1 and 2, important chiral building blocks for the preparation of several biologically active compounds, were synthesized. (S)- and (R)-1 were obtained from either one or both the enantiomers of benzylglycerol, while (S)- and (R)-2 were obtained from (R)- and (S)-isopropylideneglycerol, respectively. The novel efficient synthetic strategies, which do not follow routes already reported for the corresponding racemates, ensure very high regioselectivity and maintenance of the enantiomeric purity of the starting materials. The enantiomeric composition of the title compounds was determined by chiral HPLC or NMR. The key intermediate in the synthesis of non-racemic 1, namely 1-benzyl-2-mesyl-3-tritylglycerol, is a new high melting chiral C₃ synthon, worth considering for its stability, versatility, easy isolation by simple crystallization and, potential of configuration inversion through a simple one-pot reaction sequence.     

Asymmetric zinc-Reformatsky reaction of Evans chiral imide with acetophenones and its application to the stereoselective synthesis of triazole antifungal agents

The Ni(acac)₂ catalytic ZnEt₂-mediated asymmetric Reformatsky-type reaction of Evans chiral imide with various acetophenones was studied. The chiral imido zinc enolate, which was formed through the metal–halogen exchange reaction of chiral α-bromopropionyl-2-oxazolidinones 2 with diethyl zinc under the catalysis of Ni(acac)₂, performed the asymmetric zinc-Reformatsky reaction with activated α-haloacetophenones 3 to give the chiral β-hydroxyamide 4 in good yields and high ratios of syn-(2R,3R)-isomers (up to >97%). This new asymmetric synthesis technology affords a practical method to synthesize the versatile chiral building block 5 for triazole antifungal agents, such as Voriconazole, Ravuconazole, TAK-187, and RO-0094815.     

Asymmetric synthesis of new chiral long chain alcohols

Sixteen new chiral alcohols with alkyl (C₁₁–C₁₉) and aryl, substituted aryl, hetero aryl and biaryl groups 2a–2t were synthesized by three different asymmetric reduction methods from their corresponding ketones 1a–1t. Chiral NaBH₄ (method A), chiral BH₃ (method B) and chiral AIP (method C) were used as asymmetric reduction catalysts. Chiral NaBH₄ was modified by four different ligands 3a–3d, chiral BH₃ and chiral AIP by four different ligands 4a–4d. Ligand 4c was synthesized for the first time in this work. Chiral NaBH₄ generated chiral alcohols of (R)-configuration and chiral BH₃ and chiral AIP of (S)-configuration with high enantiomeric excesses, were analysed by chiral HPLC. In order to determine the ee values by chiral HPLC, sixteen corresponding racemic alcohols, synthesized by reducing their corresponding ketones via NaBH₄, were used for chiral resolution on a Daicel OD HPLC column. The sixteen starting ketones were synthesized in this study by Friedel–Craft acylation. The new chiral alcohols were characterized by IR, NMR, (¹H and ¹³C), MS, elemental analyses and specific rotation. The reduction methods A, B and C were applied to these ketones for the first time in this study and were compared with each other. The relationship between the structure of the ketone and the yield and the enantiomeric excess was discussed.     

Formation of chiral 21-helical columnar host system with phenylacetylene unit by using (1R,2S)-2-amino-1,2-diphenylethanol

A tunable supramolecular phenylacetylene host system with a chiral channel-like cavity is developed by using (1R,2S)-2-amino-1,2-diphenylethanol. This host system possesses a chiral 2₁-helical columnar structure; chiral cavities are constructed by the self-assembly of the 2₁-helical column, and guest molecules are included by varying the packing of this column.     

Chiral calix[4]azacrowns for enantiomeric recognition of amino acid derivatives

In this study the synthesis of novel chiral calix[4]azacrown derivatives has been reported. The enantioselectivity of chiral receptors was investigated by using UV-vis spectroscopy. All the chiral calix[4]arene derivatives exhibited certain chiral recognition toward the enantiomers of phenylalanine (Phe-OMe·HCl) and alanine methyl ester hydrochlorides (Ala-OMe·HCl). As a chiral receptor, the furfuryl-armed calix[4]azacrown ether 7 has the best enantiomeric discriminating ability for α-amino acid ester hydrochlorides (up to K_L/K_D=2.08, ΔΔG₀=−1.82 kJ mol⁻¹) in CHCl₃. The enantiomeric recognition abilities for guests are also discussed from a thermodynamic point of view.     

Control of polymorphism by crystallization of N,N-diisopropylcarbamoylisatin

N,N-Diisopropylcarbamoylisatin showed polymorphism and was crystallized into two different space groups, chiral P2₁2₁2₁ and racemic P2₁/c from the solvent; the polymorphism could be controlled by crystallization from the melt using the difference of melting points.     

Tocopherol side chain synthesis via asymmetric organocatalytic transfer hydrogenation and convenient measurement of stereoselectivity

An asymmetric synthetic route for 1-iodofarnesane, a key intermediate for tocopherol side chain synthesis, starting from (+)-(R)-citronellal was developed. 1-Iodofarnesane was prepared through eight steps in about 50% overall yield, and asymmetric transfer hydrogenation of the enal with a chiral organocatalyst was conducted as a stereoinduction step. To measure the stereoinduction level and optical purity of the product, a convenient analytical method was developed in which a phenylcarbamate derivative of the C₁₅ alcohol was found to be suitable to give proper polarity and UV-activity for chiral UV-HPLC analysis.     

Enantioselective synthesis of chiral porphyrin macrocyclic hosts and kinetic enantiorecognition of viologen guests

The construction of macromolecular hosts that are able to thread chiral guests in a stereoselective fashion is a big challenge. We herein describe the asymmetric synthesis of two enantiomeric C₂-symmetric porphyrin macrocyclic hosts that thread and bind different viologen guests. Time-resolved fluorescence studies show that these hosts display a factor 3 kinetic preference (ΔΔG^‡_on = 3 kJ mol⁻¹) for threading onto the different enantiomers of a viologen guest appended with bulky chiral 1-phenylethoxy termini. A smaller kinetic selectivity (ΔΔG^‡_on = 1 kJ mol⁻¹) is observed for viologens equipped with small chiral sec-butoxy termini. Kinetic selectivity is absent when the C₂-symmetric hosts are threaded onto chiral viologens appended with chiral tails in which the chiral moieties are located in the centers of the chains, rather than at the chain termini. The reason is that the termini of the latter guests, which engage in the initial stages of the threading process (entron effect), cannot discriminate because they are achiral, in contrast to the chiral termini of the former guests. Finally, our experiments show that the threading and de-threading rates are balanced in such a way that the observed binding constants are highly similar for all the investigated host–guest complexes, i.e. there is no thermodynamic selectivity.

Chiral guests display kinetic stereoselective threading through chiral porphyrin cages if their chirality is located at the chain ends and not in the centers, supporting the previously reported entron effect of threading.