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Surface functionalization of teeth with fluoride-incorporated apatite layers displays great potential in treatments and prevention of dental disorders. In this study, we used a sintered hydroxyapatite (sHA) substrate as a model material of teeth, and established a rapid and area-specific coating technique of fluoride-incorporated apatite layers by using a laser-assisted biomimetic (LAB) process. In this technique, a sHA substrate was irradiated on the surface with a Nd:YAG pulsed UV laser for 30 min in supersaturated calcium phosphate (CaP) solutions with various fluoride concentrations. The fluoride concentration in the CaP solution was varied to control morphology, crystalline structure, and fluoride content of the resulting layers. Without fluoride in the CaP solution, an octacalcium phosphate (OCP) layer with a flake-like structure was formed on the laser-irradiated surface of the substrate. The addition of fluoride (1000 µM and 3000 µM) to the CaP solution led to the formation of fluoride-incorporated apatite layers with an enamel-like needle-like nanostructure. The fluoride-incorporated apatite layers adhered firmly to the sHA surface and reduced acid dissolution of the sHA substrate by acting as a protective covering. Additionally, the layers released fluoride ions for more than 24 h, and exhibited antibacterial activity relative to a caries-causing bacterium, namely Streptococcus mutans. Thus, our LAB process can potentially act as a new tool for functionalization of tooth surfaces. Statement of Significance We used a sintered hydroxyapatite (sHA) substrate as a model material of teeth, and established a rapid and area-specific coating technique of fluoride-incorporated apatite layers on the sHA surface by using our laser-assisted biomimetic (LAB) process. In this process, pulsed laser was utilized to accelerate seeded crystal growth in supersaturated calcium phosphate solutions supplemented with NaF. The thus-fabricated fluoride-incorporated apatite layers consisted of enamel-like needle-like nanocrystals with c-axis orientation. These fluoride-incorporated apatite layers adhered firmly to the sHA surface, reduced acid dissolution of the sHA substrate by acting as a protective covering, and exhibited antibacterial activity against Streptococcus mutans through the fluoride release. Thus, our LAB process can potentially act as a new tool for functionalization of tooth surfaces.

Efficient synthesis of l -α-phosphatidyl- d - myo -inositol 3,5-bisphosphate was achieved from 1,2,5,6-diisopropylidene- d -glucose by utilizing ring-closing metathesis and catalytic OsO 4 dihydroxylation.

Catalytic protonation of achiral lithium enolates (derived from 2-substituted-1-tetralones), mediated by a chiral tetraamine ligand [( R , R )- N , N ′-bis[1-phenyl-2-(1-piperidinyl)ethyl]-1,3-propanediamine (0.10 equiv.)], was achieved with high enantioselectivity (up to 93% ee) by using water (10% aqueous citric acid) as a proton source. A possible mechanism of highly efficient catalytic turnover of the chiral tetraamine ligand is discussed.

Catalytic asymmetric alkylation of achiral lithium enolates of 1-tetralone and cyclohexanone with reactive alkyl halides was realized by using a combination of a chiral tetradentate amine (∼0.05 equiv.) and an achiral bidentate amine (2 equiv.).

The rate of the reaction of the lithium enolate of 1-tetralone with alkyl halides was enhanced greatly in the presence of 3 equivalents of 1,1,4,7,10,10-hexamethyltriethylenetramine. The ratio of the monoalkylated product to the dialkylated product was found to have increased under a shorter reaction time.

The 1,4-addition reaction of organolithium reagents with 2,6-bis( tert -butyl)-4-methoxyphenyl naphthalenecarboxylates gave regioselectively substituted dihydronaphthalenecarboxylates in high yields. Successive treatment of the esters with organolithiums in THF, lithium triethylborohydride, methyl iodide, and finally sodium borohydride in methanol, provided regio- and stereoselectively the corresponding 1,1,2- and 1,2,2-trisubstituted dihydronaphthalenylmethanols in good yields. This one-flask process is constituted from a sequence of five reactions involving a reductive generation of an aldehyde metal enolate from a ketene as the key step.

Enantioselective asymmetric alkylation of achiral lithium enolates mediated by chiral tetradentate amine ligands is achieved to give chiral quaternary carbon centers. Turnover of a chiral tetradentate amine in the presence of an achiral bidentate amine during the reaction is also realized.

Enantioselective alkylation of lactams and lactones can be realized up to 98% ee by deprotonation with a chiral tetradentate lithium amide (4b) in the presence of lithium bromide, and subsequent alkylation with active alkylating agents in non-chelating solvents.

An efficient enantioselective alkylation of the lithium enolates of cyclohexanone and I-tetralone with reactive alkyl halides was realized using a stoichiometric amount of a tetradentate chiral amine as a ligand for the lithium in the presence of lithium bromide in toluene.

A systematic method for 13C labeling of the glycan of immunoglobulin G for NMR study has been developed. A mouse immunoglobulin of subclass IgG2b has been used for the experiment. On the basis of chemical shift and linewidth data, it has been concluded that (1) the mobility of the carbohydrate chain in IgG2b is comparable to that of the backbone polypeptide chain with the exception of the galactose residue at the nonreducing end of the Man alpha 1-3 branch, which is extremely mobile and (2) agalactosylation does not induce any significant change in the mobility. The results obtained indicate that even in the agalactosyl from the glycans are buried in the protein. Biological significance of the NMR results obtained is also briefly discussed.

1H-NMR spectral studies have shown that lithium-hydrogen interchange between a chiral bidentate amine ( (R)- 3b ) and an achiral tridentate lithium amide (5a) occurs rapidly in THF, favoring the exclusive formation of a chiral bidentate lithium amide ( (R)- 2b ) at equilibrium. This finding was applied to catalytic asymmetric deprotonation of prochiral 4-substituted cyclohexanones (1) using 0.3 equivalent of (R)- 3b in the presence of 2.4 equivalents of 5a in THF in the presence of DABCO and HMPA.

Enantioselective deprotonation of 4-substituted cyclohexanones ( 1a∼d ) by chiral bidentate lithium amides ( (R)- 2a∼j ) having an alkyl- or a fluoroalkyl substituent at the amide nitrogen was examined. (R)- 2i having a 2,2,2-trifluoroethyl group at the amide nitrogen was found to be an excellent chiral base for the present deprotonation reaction. Structures of (R)- 2i in solution and solid state are discussed.

The diastereo- and enantioselective Michael reaction of ketone lithium enolates using a chiral amine ligand (1) was examined. Michael adducts (4) were obtained in excellent chemical yields (95∼99%) with high stereoselectivities ( syn- 4 anti- 4 : 16 84 ∼ 1 99 ; ee of anti- 4 : 81∼99 %) by the reaction between alkyl phenyl ketones (2) and Michael acceptors (3) having an alkylidene group.

6 Li- and 15 N-NMR spectroscopic analyses of a labeled chiral bidentate lithium amide ( [ 6 Li , 15 N 2 ]-(R)- 1 ) have shown that it exists as a chelated monomer ( 5 ) in THF and in DME, as a chelated dimer ( 6 ) in toluene and in ether, while as a chelated monomer ( 5 ) in any of these solvents in the presence of 2 equivalents of HMPA. Solvent-dependent enantioselectivities in deprotonation of 4- tert -butylcyclohexanone ( 2 ) by (R)- 1 appear to be correlated to these solution structures.

Enantioselective deprotonation of prochiral 4-substituted cyclohexanones (4a∼d) by chiral chelated lithium amides (8a≈k) in the presence of excess trimethylsilyl chloride was realized to give the corresponding chiral silyl enol ethers (6a∼d) in up to 89% ee. It is shown that enantioselectivity of the reaction is dependent on the solvent used, but becomes almost independent on the solvent in the presence of HMPA. The sense of asymmetric induction can be correlated to the configuration at the chiral carbon bearing amide nitrogen of the lithium amide. © 1997 Elsevier Science Ltd.

Chiral C 2 -symmetric DMEU derivatives were designed and synthesized as chiral ligands for lithium. The reaction of the lithium enolate ( 2 ) of 1-tetralone ( 1 ) with methyl iodide in toluene in the presence of a DMEU derivative ( 11 ) and hexamethyl-disilazane gave ( S )-2-methyl-1-tetralone ((S)- 3 ) in up to 92% ee.

Enantioselective deprotonation of 4-substituted cyclohexanones (1) in the presence of excess trimethylsilyl chloride was examined using chiral bidentate lithium amides ((R)-3∼(R)-7) in THF. The solution structures of (R)-3a in THF in the presence and in the absence of lithium chloride were studied by NMR. It is concluded that the eight-membered cyclic transition state (10) offers reasonable explanation of the stereochemical course of the present reaction using (R)-3a.

Lithium-hydrogen interchange between a chiral bidentate amine ((R)-4b) and an achiral tridentate lithium amide (8) occurs rapidly in situ, favoring the exclusive formation of a chiral bidentate lithium amide ((R)-5b). Based on this finding, catalytic asymmetric deprotonation of 4-substituted cyclohexanones (1a∼d) was realized by using less than a stoichiometric amount of (R)-4b as a chiral auxiliary.

Enantioselectivity of deprotonation reaction of 4-tert-butylcyclohexanone (2) by a monodentate chiral lithium amide ( (R,R)- 1 ) in THF is strongly influenced by the presence of lithium halides. Aggregation states of this chiral lithium amide in THF-d8 in the absence and in the presence of lithium halides were studied by 6Li and 15N NMR. It is concluded that the mixed dimer (D) is the species to give the high enantioselectivity of the reaction.

The enantioselective Michael reaction of ketone lithium enolates using a chiral amine ligand ( 1 ) was studied. Michael adducts ( 4 ) of up to 94% ee were obtained by the reaction between methyl ketones ( 2 ) and Michael acceptors ( 3 ) having a benzylidene group.

In the presence of the palladium complex with the phosphorus-containing C2-symmetric chiral amine ligand 2, 3, the asymmetric allylic substitution of racemic 1,3-diphenyl-2-propenyl acetate 8 with dimethyl malonate proceeded in high yield with remarkable enantiomeric excess.

A pyridine derivative (3) and TsOH form a 2 + 2 salt with six hydrogen bonds in the solid state, although there are equilibria between some aggregation states induced by hydrogen bonding in solution.

An asymmetric 1,2-addition reaction of organolithiums with imines 3, 7 was catalysed by a 0.05–1.3 equivalent of a chiral amino ether 2 to provide the corresponding optically active amines 4, 8 .

Enantioselective total synthesis of (+)-stoechospermol 2, a representative of spatane diterpenes having a cis,anti,cis-tricyclo[5.3.0.02,6]decane skeleton, was achieved by employing a stereo- and regioselective intramolecular (2+2) photocycloaddition of (S)-γ-hydroxymethyl-γ-butenolide-derived ester 10.

Chlorotrimethylsilane promoted asymmetric Michael reaction of the chiral lithioenamines derived from α-alkyl β-keto esters and ( S )-valine tert -butyl ester is described. Complementary asymmetric syntheses producing either enantiomers from the same starting material have been realized by changing the solvent system. That is, the lithioenamines react with methyl vinyl ketone or ethyl acrylate in THF in the presence of chlorotrimethylsilane to give, after hydrolysis, the Michael adducts in 57–90% ee. On the other hand, the reaction using toluene-HMPA as a solvent system, instead of THF, affords the corresponding antipodes with enantiomeric purities of 41–77% ee.

A C2-symmetric chiral diamine ligand 1 was found to be effective for palladium catalyzed asymmetric allylic substitution of racemic 1,3-diphenyl-2-propenyl acetate 5 with dimethyl malonate. The X-ray analysis and NMR study of the palladium complex 7 with chiral diamine 1 have revealed the mechanism of high enantioselection.

Mono-deuterated derivatives of optically active 3-keto steroids ( 4 -2α-d, 4 -2β-d, 5 -4α-d, 5 -4β-d, 6 -2α-d, and 6 -2β-d) were treated with a chiral lithium amide (( S )- or ( R )- 2b ) in the presence of excess trimethylsilyl chloride to give the corresponding diastereomeric Δ 2 - and ΔA 3 -silyl enol ethers. It is concluded that the present deprotonation reaction occurs in chair conformation in 6 , while in boat (skew-boat) conformation about the A-rings in 4 and 5 .

Chiral chelated lithium armides (2e∼h) having a fluorine-containing alkyl group on amide nitrogen were found to induce high enantioselectivity in kinetic deprotonation of 4-substituted cyclohexanones (1a∼2d).

Optically active and racemic azaisopicrostegane ( 3 ), azapicrostegane ( 4 ), and all of four stereoisomers of racemic azaisopicrosteganols and azapicrosteganols ( 5, 6, 8, 9 ) were successfully synthesized by oxidative coupling of dibenzylurethanes ( 12, 18, 19 ).

Diastereoselective alkylation of chiral lithium enolates (dl-, (R)- and (S)-9) derived from 4-t-butylcyclohexanone in the presence of a chiral seco

Enantioselective 1,2-addition of Grignard reagents to aldehydes using chiral diamine 1, 2 was examined. High ee (up to 75 %) of carbinol was achieved by the reaction of arylmagnesium bromide and benzaldehyde with chiral diamine. Utilizing 2,4,6-trimethylphenoxyaluminum dichloride 6 as a coordinating agent to benzaldehyde, enantioselectivity of the addition of alkylmagnesium bromide was dramatically increased (up to 70 %).

Asymmetric alkylation reaction of chiral enamines prepared from α-alkyl β-keto esters and ( S )-valine tert -butyl ester leading to either enantiomer is described. Lithiated chiral enamines can be alkylated with alkyl halides in a toluene solvent in the presence of HMPA to give, after hydrolysis, α,α-dialkyl β-keto esters in 70–99%ee. The reactions in the presence of THF, dioxolane, or trimethylamine, instead of HMPA, afford the corresponding antipodes with enantiomeric purities of 44–92%ee. The present method provides a procedure for the synthesis of both enantiomers of α,α-dialkyl β-keto esters in high enantiomeric purities starting from the same chiral enamines.

Novel chiral pyrrolidine-based diamines with C2-symmetry 2, 3 and their related compounds 4 – 8 were designed and synthesized in optically pure forms. Both (+)- and (−)-2 were prepared from optical active ditosylane 9. 3 was prepared from 3,5-dimethylbenzaldehyde through optical resolution and its absolute stereochemistry was correlated with 2,3-dimethylsuccinate 27. 4 was prepared from (−)-diol 28. 5 – 8 were prepared from 9 and 11.

Short-step asymmetric syntheses of (+)-7-dehydroxy-4-demethoxydaunomycinone 4 and (−)-9-deacetyl-7-dehydroxy-4-demethoxy-9-hydroxymethyldaunomycinone 5 were accomplished via enantioselective dihydroxylation by osmium tetroxide with chiral diamine 13.

Based on the concept of a metal differentiating coordination, a new chiral amidophosphine ligand 2 was designed, synthesized, and applied in an enantioselective conjugate addition of lithium dimethylcuprate to chalcone providing the corresponding adduct in 84% ee.

Negatively-charged cyclophanes ( 2a,2b ) having eight carboxylate groups on the aromatic rings were designed and synthesized. It is shown that they work as hosts that form inclusion complexes selectively with positively-charged aromatic compounds as guests in alkaline water.

An asymmetric 1,2-addition of organolithiums to imines (1) was catalyzed by a substoichiometric amount (0.05-0.3 equivalent) of a chiral aminoether (2) to provide the corresponding optically active amines (3).

Total synthesis of dolastatin 10 (1) was completed by developing an efficient synthesis of two key amino acid components, Dil (6) and Dap (11), and subsequent stepwise coupling of five amino acid components from C-terminal Doe.

The Maillard reaction was done with several proteins and aldoses (glucose, glyceraldehyde, and glycolaldehyde) under both neutral and alkaline conditions. Maillard reaction products (MRP) from αs-casein and albumins (ovalbumin, bovine serum albumin, human serum albumin, and α-lactalbumin) inhibited adhesive insoluble glucan synthesis by glueosyltransferase (GTF) of Streptococcus mutans. The magnitude of the inhibitory activity in MRP from αs-casein and the three aldoses correlated with the reactivity of the aldoses with proteins. The MRP from αs-casein and albumins inhibited GTF-I and did not affect GTF-S, while their original proteins stimulated GTF-I specifically. These results suggest that the inhibitory activity of these MRP may be related to the GTF-I stimulating property of their original proteins.

An attempt was made to accelerate intramolecular amide bond formation by introducing additional catalytic groups to the crown ether having two thiol groups as the enzyme model for the peptide synthesis. The host with methyl ester groups performed the reaction more effectively than that without them. It has been suggested that the ester groups can achieve acceleration through their preorganization in the crown host.

The reaction of methyllithium with 4-methoxyphenylimine of 1-naphthalenecarbaldehyde (1) in the presence of the chiral ligand A afforded, contrary to 1,4-addition with the cyclohexylimine, the corresponding 1,2-addition product as an optically active amine (2) in 70% ee.

[Structure: see text] A novel alicyclic chiral C2-symmetric piperazine, (S,S)-7, is designed and synthesized from L-proline. Benzoylation of a series of cyclic and acyclic meso-1,2-diols with a catalytic amount of (S,S)-7 and CuCl2 provided optically active monobenzoates with high enantioselectivity.

beta-N-Acetylhexosaminidase was produced by Trichoderma harzianum cultivated with chitin as the growth substrate. The enzyme was purified 13.2-fold to homogeneity by ultrafiltration and sequential chromatography on SP-Toyopearl and Sephacryl S-200. The molecular weight of the enzyme was estimated to be about 150,000 by gel filtration. The pH and temperature optima were 4.0-5.5 and 50 degrees C, respectively. The enzyme hydrolyzed N-acetylchitooligosaccharides at the non-reducing ends to release GlcNAc monomer. The enzyme showed a strict substrate specificity to the sugar chains in complex carbohydrates, hydrolyzing only the linkage of GlcNAc beta 1-3Gal, but not hydrolyzing the other linkages such as GalNAc beta 1-3Gal and GlcNAc beta 1-2Man.

Oxidation of a cytotoxic podophyllotoxin aza-analogue 2 into the quinone 3 succeeded in acquiring DNA topoisomerase II inhibitory activity at a concentration of 25 μM due to stabilization of the cleavable complex.

An α-phenethylamine-derived chiral lithium amide ( (R) - 5c ) possessing a 2,2,2-trifluoroethyl group on the amide nitrogen was found to induce high enantioselectivity in the kinetic deprotonation of 4- tert -butylcyclohexanone ( 1 ) in the presence of excess trimethylsilyl chloride to give the corresponding silyl enol ether ( (S) - 2 ) in up to 92% ee (86% chemical yield). © 1997 Elsevier Science Ltd.

Aerobic oxidative coupling of 2-naphthol derivatives by the use of 1 mol% of CuCl-amine complex afforded binaphthol derivatives in excellent yields.

In the Presence of both stoichiometric and catalytic amounts of a chiral dieter 1, aryllithiums reacted with BHA-esters of naphthalenecarboxylic acids 2, 5 to afford the corresponding adducts 4, 6 in high ee.