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N-tert-Butoxycarbonylcarbamates of α-amino acid derivatives underwent asymmetric carbonyl migration by treatment with KHMDS in DMF to give α-amino acid derivatives with an additional ester group at the newly formed tetrasubstituted carbon center in up to 99% ee.

Several types of host molecules based on a phenolphthalein (one of the most popular pH indicators) and two crown ethers were prepared for use in colorimetric recognition of linear diamines, triamines, sequence of non-protected dipeptides, and chirality of alanine derivatives in methanol or water solution. Especially, host 30 with a dimethylamino group showed excellent selectivity for spermidine and spermine among other biogenic amines and high sensitivity.

Asymmetric Horner–Wadsworth–Emmons reactions of selected meso -α-dicarbonyl compounds with chiral phosphonate reagents, which possessed axially dissymmetric 1,1′-bi-2- or 8-naphthol at the carboxylate moiety as a chiral auxiliary, were examined. The reactions proceeded smoothly with good chemical yields as well as with high diastereoselectivities. Z -olefins were preferentially formed, and it was found that the free hydroxy group at the 2′- or 8′-position on the naphthalene ring plays a crucial role in the high diastereoselectivity, probably due to a complex-induced proximity effect. Mechanistic considerations are also described.

Chiral 2,2′-dimethyl-1,1′-binaphthyl-8,8′-diamine 3b was synthesized via a diastereomeric resolution and determination of the absolute configurations, and the barriers compared for atropisomerization amongst binaphthyl skeletons.

Host 1 based on the phenolphthalein skeleton and two crown ether moieties demonstrated opposite behaviors toward sodium and potassium cations caused by bidirectional complexation. [reaction: see text]

The oxidative homocoupling of optically active binaphthalenes 1a−d with a stoichiometric amount of CuCl2 and amines afforded quaternaphthalenes 2a−d in up to 93% de. The high diastereoselectivities were achieved through three different pathways (epimerization of the axis together with diastereoselective crystallization, thermodynamic, and kinetic control pathways). The type of side chains on the naphthalene influenced which pathway dominates. Three pathways were applicable to octinaphthalenes (8a−d) and hexadecanaphthalene 10a with 46−99% de. The absolute configuration of the newly formed axial bond was determined by (1) X-ray crystallographic analysis, (2) transformation to known compounds 15 and 16, (3) CD spectra of oligonaphthalenes with two pyrene rings as exciton parts, and (4) the shift values in 13C NMR spectra of 13C-enriched derivatives 29−31 toward chiral shift reagent Eu(+tfc)3.

Various types of chiral host molecules 2−7 based on a phenolphthalein skeleton and two crown ethers were prepared for use in visual enantiomeric recognition, and we examined their enantioselective coloration in complexation with chiral amino acid derivatives 9−22 in methanol solution. Methyl-substituted host (S,S,S,S)-3 showed particularly prominent enantiomer selectivity for the alanine amide derivatives 11 and 12. A combination of methyl-substituted host (S,S,S,S)-3 with guest (R)-11 or (R)-12 developed a purple color, whereas no color development was observed with (S)-11 or (S)-12. On the other hand, phenyl-substituted host (S,S,S,S)-6 showed deeper coloration with a wide range of (S)-β-amino alcohols compared to that seen with host (S,S,S,S)-6 and the corresponding (R)-β-amino alcohols at 0 °C. Furthermore, absorbance inversion temperatures (AIT) were observed within the range of 0−50 °C in many cases.

An efficient and convenient method for the synthesis of chiral triamines with two substituents at the α position to the terminal amino group (spermidine analogues) is described. These chiral N , N -bis(4-substituted-4-aminobutyl)amines may have anticancer activities.

The copper mediated oxidative coupling of optically active quaternaphthalenes having a 2-hydroxynaphthyl moiety gave configurationally defined optically active octinaphthalenes. The absolute configuration was determined by comparison with products of [6+2] coupling. The CD spectra of bi-, ter-, quater-, sexi- and octinaphthalenes suggested that the absolute configuration of the chiral axis could be deduced from the intensity of their Cotton effects.

The synthesis and resolution of 3,3′-bis(benzyloxy)-1,1′-binaphthalene-2,2′-diol 1 is described. A diastereomeric mixture of 7 (derived from (±)- 1 and Boc-Ala-OH) was separated using crystallization and column chromatography.

Two binaphthyl crown receptors containing phenylboric acid 2 and 2,4-dinitrophenylurea 3 as lariat parts were prepared from the optically active binaphthyl crown alcohol 1 in two and four steps, respectively. Host 2 showed a 30% extraction efficiency for GABA by a solid–liquid extraction method in DMSO. Chromogenic Host 3 discriminated the guest linear amino acid by molecular length and the information was revealed through color changes.

Homooxacalix[3]arene derivatives are effective ionophores for constructing serotonin-selective membrane electrodes. An electrode based on one of the derivatives, tris(methoxyphenylpropyloxy)hexahomooxacalix[3]arene-triethyl ether, with potassium tetrakis(p-chlorophenyl)borate (20 mol% relative to the ionophore) as an ionic additive and bis(2-ethylhexyl) sebacate as a solvent mediator in a poly(vinyl chloride) membrane matrix, displayed much better selectivity for serotonin than for various organic ammonium ions and inorganic cations. The electrode exhibited a near-Nernstian response to serotonin in the concentration range of 2×10−4 to 1×10−2 M with a slope of 56.4 mV per concentration decade in physiological saline containing 150 mM NaCl and 10 mM Na2HPO4/NaH2PO4 (pH 7.4). The limit of the detection was 8×10−5 M. The selectivity pattern of this electrode was quite different from that of an electrode using calix[6]arene-hexaacetic acid hexaethyl ester, a well-known ionophore for primary organic ammonium ions, which did not induce an enhanced response to serotonin. The developed electrode was used for the active loading of serotonin in liposomes induced by transmembrane pH gradients.

Chiral 4-pyrrolidinopyridine analogues 8 – 13 with two distinct functional side chains at C(2) and C(4) of the pyrrolidine ring were prepared from 4-hydroxy- l -proline. We examined desymmetrization of meso -1,3-cyclohexanediol through enantioselective acylation using these catalysts and found that introduction of a C(4)-side chain was effective for improving both the chemo- and enantioselectivity of acylation.

Two strategies were introduced for the control of enantioselectivity of alkylation of phenylalanine derivatives by regulation of the aggregate structure of chiral enolate intermediates. Use of amino acid-dimers, 6 and 15 , was effective to minimize solvent- and electrophile-dependency of enantioselectivity of the alkylation. α-Allylation of 20 proceeded in improved selectivity of 82–88% ee under the control of aggregation of the intermediary enolate.

Optically active tetrahydroisoquinoline and tryptoline derivatives with a quaternary carbon center at C(3) were prepared from L-DOPA and L-tryptophan, respectively.

The new ditopic receptors 1–3 consisting of a meso-ternaphthalene backbone and two crown ether rings have been synthesized. Hosts 2 and 3 have been shown to selectively complex and transfer the dipicrates, 1,9-diaminononane and 1,10-diaminodecane, from aqueous solution into the organic phase.

[structure: see text] A receptor 1 with phenolphthalein and two crown ethers in the molecule develops brilliant purple color in the presence of dipeptides with a specific amino acid-sequence containing a C-terminal lysine. This type of color development could be extended to the detection of oligopeptides of a specific sequence at the N-terminal such as scyliorhinin I and APP(770)(394-410).

Intramolecular asymmetric Wittig-type reactions of some chiral binaphthyl phosphonates of 2,2-disubstituted 1,3-dicarbonyl derivatives were investigated. The base-mediated cyclization occurred with differentiation of two diastereotopic carbonyl groups to give non-racemic dihydronaphthalene derivatives with moderate to good enantiomeric excess. The degree of asymmetric induction depended upon the substrates and the best result was obtained with the indanedione derivatives having alkyl substituents in 58–73% yield with 82–88% e.e. The absolute structure of one of the products was unambiguously determined by X-ray analysis and some mechanistic consideration is also given.

Novel perhydro-indanones and -naphthalenones having a quaternary stereogenic carbon and tetrasubstituted olefinic linkage were prepared via asymmetric intramolecular Horner–Wadsworth–Emmons reactions. The optically active binaphthyl phosphonates were connected with the 2-substituted cyclopenta- or cyclohexa-1,3-dione through the linker arm and the successive base treatment of the products with diethylzinc led to cyclization reactions with concomitant differentiation of diastereotopic carbonyl groups to afford the non-racemic title compounds in good enantiomeric excess. The absolute structure of the cyclized product was determined by X-ray analysis of its derived bromide.

An optically active proton-ionizable lariat crown ether derivative 2 was prepared. Host 2 displays enantiomeric selectivity toward phenylglycinol (Klarge/Ksmall=3.2) and phenylalaninol (Klarge/Ksmall=1.7). The key intermediate 1 was synthesized in two steps from commercially available binaphthol in 30% yield.

A new ditopic receptor 2 consisting of a meso-ternaphthalene backbone and two crown rings has been shown to selectively complex and transfer dipicrate of 1,9-diaminononane and 1,10-diaminodecane from aqueous solution into the organic phase.

N-Boc-N-MOM-α-amino acid derivatives (Phe, Val, Leu, His, Trp, Tyr, Dopa) underwent asymmetric α-methylation in 76-93% ee by treatment with KHMDS followed by methyl iodide in the absence of any external chiral source. A chiral nonracemic enolate with dynamic axial chirality is proposed as the crucial intermediate whose racemization barrier is 16.0 kcal/mol and the corresponding half-life is 22h at -78°C.

The chiral phosphonoacetate (S)-1 can discriminate between the enantiotopic dicarbonyls of η6-arene Cr and η4-diene Fe complexes to afford optically active olefins with planar chirality in high enantiomeric excess and good yield. An analogous reagent (S)-2 was used for kinetic resolution of a racemic mixture of the aldehyde of the Fe η4-diene, which resulted in formation of the corresponding olefin together with the recovered aldehyde in high enantiomeric excess. The absolute stereostructures of these adducts were determined by X-ray analysis with anomalous dispersion of metals.

The diastereomeric mixture of monoesters of racemic 8,8'-dihydroxy-1,1'-binaphthyl and N-CBZ-L-proline was easily separated. Each diastereomer gave enantiomerically pure (R)- or (S)-8,8'-dihydroxy-1,1'-binaphthyl in good yields after hydrolysis. (C) 1999 Elsevier Science Ltd. All rights reserved.

Lewis acid-promoted nitroolefination of enol silyl ethers has been developed. Enol ethers 1, 4, 5, and 6 derived from lactones and lactams furnished nitroolefines 2, 7, 8, and 9, respectively in 60-99% yields by the treatment with 3 in the presence of Lewis acids. Asymmetric nitroolefination of 5a and 6a with 12 gave 8a and 9a in 75% and 73% ee, respectively.

New methods for asymmetric reactions developed by the author's group are outlined. They include asymmetric nitroolefination through an addition-elimination process, asymmetric synthesis utilizing 2,2'-disubstituted and 8,8'-disubstituted binaphthyl derivatives, and enantioselective alpha-alkylation of carbonyl compounds under conditions with absolutely no external chiral environmental factors.

Hexahomooxacalix[3]arenes 1 bearing different substituents on their upper rim were synthesized from the corresponding linear trimers 2 by the acid-catalyzed cyclization. The X-ray crystallographic analyses of 1 (R1 = R3 = H, R2 = t-Bu, and R1 = Et, R2 = t-Bu, R3 = i-Pr) revealed that they adopt a cone conformation, owing to an intramolecular hydrogen-bonded network in the solid state.

Both enantiomers of the molecular bevel gear 1 having only two cogs on each wheel consisting of 8,8′-disubstituted 1,1′-binaphthyl ether were synthesized for the first time.

The Wittig reaction and its variants produce no sp3 stereocenter, nevertheless asymmetric transformation from achiral carbonyl compounds can be achieved by using optically active phosphorus reagents. These approaches are based on three different methodologies, kinetic resolution and discrimination of either π-face of carbonyl or enantiotopic carbonyl groups in the symmetrical molecules. A variety of phosphorus reagents has been reported and used for these transformations. Among the Horner-Wadsworth-Emmons (HWE) type reagents, those possessing 8-phenylmenthyl or binaphthyl groups as a chiral auxiliary exert high level of asymmetric induction. For example, the HWE reagent of binaphthyl group effectively discriminated the carbonyl face giving dissymmetric olefins, and differentiated enantiotopic carbonyls of meso-α-diketones to afford the Z- and E-olefins with high optical yield. This discrimination was successfully applied to the practical one-pot procedure for optically active allenic compounds as well as the construction of the fused ring systems through the intramolecular HWE reaction.

Diastereoselectivity in the aldol and the conjugate additions of 2′-hydroxy-1,1′-binaphthyl ester enolates with a variety of carbonyl electrophiles has been examined. The ester enolate generated by BuLi reacts with several aldehydes to give the threo products preferentially with high diastereoselectivity and in good yield. Satisfactory diastereoselectivity has also been observed in the minor erythro derivatives. A mechanistic interpretation of the results is made on the basis of the absolute stereochemistry of the products.

A chiral HWE reagent reacted with an alternative carbonyl group of meso-α-diketones of bicyclo[2.2.1] system to give non-racemic (Z)- and (E)-olefins, respectively.

The Diels-Alder reactions of unsymmetrical maleate 2 and fumarate 10 possessing axially chiral 8,8′-dihydroxy-1,1′-binaphthalene 1 with cyclopentadiene were investigated under various conditions in the presence of a Lewis acid. Both the diastereo- and endo / exo -selectivities depended on the Lewis acid used. A notably high level of diastereoselection was achieved with TiCl(O i Pr) 3 for the endo adduct of the maleate, and with SnCl 4 for that of the fumarate. The results suggest that the free hydroxyl group of the auxiliary plays a crucial role in inducing the high level of diastereoselectivity in these cycloadditions.

The effects of positive charge density on the liposomal surface on the disposition kinetics of liposomes in rats were investigated. The cationic liposomes with zeta potentials of about +15 mV remained in the blood longer than did the neutral liposomes, and the hepatic uptake of these liposomes decreased. The blood clearance of the liposomes with zeta potentials under +10 mV was comparable to that of the neutral liposomes. In contrast, the blood circulation of the liposomes with a higher positive charge density, above +25 mV, was shortened and their hepatic uptake was almost the same as that of the neutral liposomes. The optimum value of positive charge density on the liposomal surface to prolong the residency of liposomes in the blood circulation was thus determined. A liver perfusion experiment showed that the uptake of cationic liposomes with a zeta potential of about +15 mV was effectively suppressed in the presence of erythrocytes, while that of liposomes with a higher zeta potential were little affected. Thus, above +15 mV, the suppressive effect of erythrocytes on the hepatic uptake of cationic liposomes decreased with the increase of the positive charge on the liposomal surface. These results cannot be explained by the binding model, and we therefore propose the ionic atmosphere model: Cationic liposomes surround the erythrocytes with a negative surface charge like the ion atmosphere of the Debye-Huckel theory. The cationic liposomes with a suitable positive charge surround the erythrocytes as an ionic atmosphere and could then escape the reticuloendothelial system (RES). The higher positively charged liposomes were taken up by the liver probably due to the shield of the negative charge of erythrocytes provided by the cationic liposomal atmosphere.

The uptake of liposomes by rat liver was investigated by perfusion. Positively and negatively charged liposomes were taken up to a greater extent than neutral liposomes in Hanks' buffer. However, the uptake of cationic glucosamine-modified (PG1cN) liposomes was suppressed when blood was added to the perfusate, while the uptake of negatively charged phosphatidylserine (PS) and neutral liposomes was enhanced, probably due to the action of opsonins. The uptake of cationic PG1cN-liposomes by the liver was suppressed when red blood cells were added to the perfusate, while uptake was little affected in the presence of serum. These results revealed that rat erythrocytes play an important role in the capacity of cationic liposomes to avoid uptake by the reticuloendothelial system (RES). Cationic PG1cN-liposomes bound to rat erythrocytes weakly; however, the zeta potential of erythrocytes increased in the presence of cationic PG1cN-liposomes and showed homogeneous distribution. Cationic PG1cN-liposomes may surround the erythrocytes with an ionic atmosphere. Cationic PG1cN-liposomes would interact with erythrocytes through electrostatic interaction and could thus escape phagocytosis by macrophages.

A monofatty acid ester of glucosamine (PGlcN) was synthesized to provide liposomal membranes with a positive charge, and the trapping efficiency of negatively charged substances (superoxide dismutases, SODs) into cationic liposomes containing PGlcN or stearylamine (SA) prepared by various methods was compared to find the most efficient trapping methods. We demonstrated that cationic liposomes, which were prepared in a buffer of low ionic strength containing sorbitol by a simple hydration method, could entrap a large amount of negatively charged SODs which retained their activity, as compared with cationic liposomes prepared in a buffer of high ionic strength. We also showed a reverse-phase evaporation method entrapped a large amount of SODs. However, SODs were inactivated during the preparation; therefore, this method was not suitable to entrap the enzyme. Freeze-thaw method induced the formation of cationic liposomes which were smaller than extruded liposomes and could entrap the SODs in a buffer of low ionic strength. Dehydration-rehydration method with a buffer of low ionic strength also entrapped a large amount of SODs, indicating that the integrity of liposomes was lost in the lipid bilayer after freeze-drying and the SODs were entrapped in the reconstruction of liposomes during rehydration. These findings showed that the hydration method based on electrostatic attraction with a buffer of low ionic strength was simple and the most effective for entrapping SODs without loss of their activity.

Half esters (R)-5 of 1,1'-binaphthalene-8,8'-diol undergo 1,4-addition of lithium dialkyl cuprates followed by formal 1,2-addition to give beta-substituted ketones (S)-6 or (S)-7 with high enantioselectivity (96 similar to 100% ee). A brief discussion of the mechanism is presented. Copyright (C) 1996 Elsevier Science Ltd

Azamacrocycles 1–4 were synthesized from 9 in 20–30% overall yields. Compounds 1 and 2 extracted some metal ions into organic solvents, but 3 and 4 did not. The crystal structure of the Ag(I) complex of 1 has been determined.

Oxidative coupling reactions of the stereochemically defined S -tetrahydroxybinaphthalene derivative gave a separable mixture of two diastereomers of the quaternaphthalenes of S , S , S and S , R , S configurations, whose stereostructures were confirmed by an alternative chemical transformation through the ternaphthalenes as well as the X-ray structure analysis. The CD spectra of the corresponding diastereomers were indicative of the stereochemistry across the axis.

Optically active 1,1′-binaphthalene-8,8′-diol is found to bind a variety of amines in CDCl3 or C6D6 solution. Significant chiral recognition (ΔΔG° = ∼1.2 kcal/mol) was observed in the valine derivative 4. A three-point binding motif is assumed.

For the purpose of practical preparations of a variety of enantiomerically pure uncommon α-amino acids, alkylations of the chiral glycine equivalent 5 , which possesses axially chiral binaphthol as an auxiliary, with several electrophiles were investigated. The alkylation proceeded smoothly in satisfactory chemical yield with high diastereoselectivities to give protected α-amino acid derivatives. The free hydroxyl group of the auxiliary played an important role for the induction of diastereoselectivity. Using ( S )-1,1′-binaphthalene-2,2′-diol as a chiral auxiliary, D-α-amino acid derivatives having the unnatural ( R )-configuration were predominantly obtained. Some of the alkylated products were converted into free non-proteinogenic D-α-amino acids.

Optically active 4,4-disubstituted conjugated allenecarboxylates were enantioselectively prepared via CC bond formation through an asymmetric Horner-Wadsworth-Emmons reaction with an optically active phosphonoacetate reagent.

A total synthesis of (-)-eserethole (2) has been accomplished using the Diels-Alder reaction of (S)-(-)-2-methyl-2- [Z-(E)-nitroethenyl]-delta-valerolactone (3) and Danishefsky's diene as a key step, The synthesis of optically pure (-)-eserethole (2) constitutes a formal synthesis of naturally occurring Calabar bean alkaloids, such as (-)-physostigmine (1), (-)-physovenine (17) and(-)-geneserine (18).

The structures of two new diterpenoids, taxchinin L (1) and taxchinin M (2), from the leaves and stems of Taxus chinensis var. mairei were elucidated by means of NMR spectroscopy. These diterpenoids have an 11(15-->1)-abeo-taxane skeleton and exist as an equilibrium mixture of two conformers in CDCl3 at an ambient temperature.

Several diazapyrene-tagged oligodeoxynucleotides were synthesized and characterized. The interaction of these modified oligomers with complementary strands indicated that introduction of the diazapyrene moiety increased the stability of the duplex as compared to that of native oligomers. DNA cleavage experiments with diazapyrene-tagged oligomers induced localized scission at the duplex region.

Asymmetric reductions of methoxy substituted 2-tetralones were studied. The asymmetric transfer hydrogenation reaction developed by Noyori using chiral η6-arene–ruthenium complexes (arene = p-cymene or benzene) was found to efficiently reduce various methoxy substituted 2-tetralones with >80% ee. Their enantiomeric excesses were found to depend on the position of the methoxy group and the types of the arene complexes. The conditions were identified for the asymmetric reduction of 8-methoxy-2-tetralone to the corresponding 2-tetralol in 98% ee, which was notably higher in enantioselectivity than the other methoxy substituted 2-tetralones.