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Piscidin 1 (Pis-1) from hybrid striped bass possesses antibacterial activities with high cytotoxicity. Previously, we reported that Pis-1[NkG], where Gly8 was substituted with positively charged Lys peptoid in Pis-1, shows high antibacterial activity with more potent bacterial cell selectivity than parent Pis-1 and Pis-1[PG] with Pro substitution at Gly8. Here, we investigated the effects of hydrophobic peptoid substitutions on antimicrobial activity and cytotoxicity of Pis-1. We designed Pis-1[NaG] and Pis-1[NlG] peptides, where Gly8 was replaced with alanine or leucine peptoids. Although hydrophobicity was increased in Pis-1[NaG] and Pis-1[NlG] compared with that in Pis-1[NkG], Pis-1, and Pis-1[PG], these peptides retained high antibacterial activity and showed no hemolytic activity when used at 100 μM. All peptoid-substituted peptides penetrated well the bacterial membrane and localized inside of the cytoplasm, while Pis-1 and Pis-1[PG] depolarized membrane severely. The flexible hinge structure formed by peptoid residues compared with the rigid bent structure formed by proline may explain their differential mechanisms of action. Most hydrophobic peptide, Pis-1[NlG], showed the most efficient inhibition of LPS (lipopolysaccharide)-induced nitric oxide production, indicating that it can be a potent antimicrobial peptide with anti-inflammatory activities. Peptoid substitution may facilitate the development of potent peptide drugs with bacterial cell selectivity.

A novel methodology for the asymmetric synthesis of trans-3,4-diaryl-substituted tetrahydroquinolines via sparteine-assisted stereoselective lithiation of o-substituted N-pivaloylanilines (I), kinetic resolution of epoxides in substitution and a stereospecific Mitsunobu cyclization is developed.

The (+)-sparteine-mediated lithiation–substitution of o-benzyl-N-pivaloylaniline with various ketones was investigated. The obtained highly enantioenriched tertiary alcohols were used for the synthesis of alkenyl-substituted products 12 and 13 as well as 3,3,4-trisubstituted tetrahydroquinoline derivatives 22–24. The reaction with α,β-unsaturated ketones afforded highly enantioenriched 1,4-addition products 28–33 and provided a protocol for the asymmetric synthesis of highly substituted tetralin derivative 34.

For asymmetric synthesis of α-substituted carboxylic acid derivatives, a variety of chiral auxiliaries have been used for the dynamic resolution of α-halo esters in nucleophilic substitution. 1 For example, L-lactamide-mediated dynamic kinetic resolution of α-bromo esters was successfully used for the asymmetric preparation of α-aryloxy carboxylic acids and oxazin-2-ones. 2 However, the application of Llactate as a chiral auxiliary was not effective for the dynamic resolution of α-halo esters. 3 In our continuous efforts to develop L-lactic acid as a chiral auxiliary for the dynamic resolution, we have recently found successful results with ethyl L-lactate. We herein report ethyl L-lactate-mediated dynamic kinetic resolution of α-bromo esters for the asymmetric preparation of α-amino acid derivatives. Treatment of racemic α-bromo-α-phenylacetic acid with ethyl L-lactate in the presence of DCC and DMAP provided α-bromo-α-phenyl ester (αRS)-1 with 50:50 diastereomeric ratio (dr) in 78% yield. When the diastereomeric mixture (αRS)-1 was treated with p-anisidine (p-MeOPhNH2, 1.5 equiv), tetrabutylammonium iodide (TBAI, 1.0 equiv) and diisopropylethylamine (DIEA, 1.0 equiv) in CH2Cl2 at room temperature for 24 h, the amino acid derivative 2 was produced in 86% yield with 97:3 dr as shown in Scheme 1. Following removal of L-lactate chiral auxiliary with Et3N in MeOH gave methyl phenylglycinate (R)-3 with 97:3 enantiomeric ratio (er) in 65% yield. 4 These results imply that α-bromo stereogenic center is configurationally labile with respect to the rate of substitution and (αRS)-1 is dynamically resolved in the substitution with the amine nucleophile. In a solvent screen, the reactions in CHCl3, ether, n-hexane and THF provided (αR)-2 with the same dr as in CH2Cl2, while the lower selectivities of 92:8 dr and 93:7 dr were observed in the reactions in DMF and CH3CN, respectively. In order to understand the asymmetric reaction pathway, we carried out two reactions with α-bromo-α-phenyl ester 1 of 67:33 dr. When 1 of 67:33 dr was allowed to reach thermodynamic equilibrium in the presence of DIEA, the diastereomeric ratio of recovered 1 was determined to be 49:51 dr. The result indicates that the thermodynamic stabilities of two diastereomers are almost the same, ruling out dynamic thermodynamic resolution as a primary pathway. In the reaction of 1 (67:33 dr) with p-anisidine under the same condition, 2 was obtained with the same stereoselectivity (97:3 dr) as in the reaction of 1 with 50:50 dr. In other words, the dr of product 2 is not dependent on the initial dr of 1. These preliminary results indicate that the epimerization is sufficiently fast with respect to the rate of substitution and the primary pathway of the asymmetric induction is a dynamic kinetic resolution. 1

Highly enantioenriched trans-2,3-disubstituted indolines have been prepared by Mitsunobu cyclodehydration of the amino alcohols obtained from (−)- or (+)-sparteine-mediated lithiation–substitution of ortho-alkyl substituted N-pivaloylanilines. Optimized cyclodehydration conditions are described, from which the combination of DEAD and PBu3 in CH3CN provides the best results.

The novel catalysts (I) and (II) are prepared and derivative (Ia) is found to be the most efficient one for the addition of ZnEt2 to aldehydes.

A novel series of carbazole-based α-aminophosphonates were synthesized by three component coupling of 6-bromo-9-ethyl-9H-carbazole-3-carbaldehyde, amine and diethyl phosphite using polyethylene glycol (PEG-400) as a green reaction media. The antiproliferative activity of these molecules was evaluated against three cancer cell lines. Of these, compounds 4c, 4e and 4m were found to exhibit good antiproliferative activity against three cancer cells, A549, MCF-7, and NCI-N87.

Styrylpyridazinone (I) has fluorescence characteristics appropriate for imaging Aβ aggregates.

The modular nature of dipeptide catalysts (I) allows for convenient fine-tuning of their catalytic activity in the dimethylzinc addition towards aromatic aldehydes (II).

A novel method for asymmetric synthesis of trans-2,3-disubstituted indolines has been developed. The strategy involves the (−)-sparteine-mediated electrophilic substitution of 2-benzyl N-pivaloylaniline with aromatic or α,β-unsaturated aldehydes and subsequent intramolecular nucleophilic substitution. The simple protocol for two-step process can produce highly enantioenriched indolines 3a–o up to 98:2 er.

Stereoselective substitution of auxiliary-bearing α-halo esters with ethylenediamine derivatives and subsequent spontaneous cyclization proceeds with dynamic resolution to afford 3-substituted piperazinones (III) in up to 88% optical purity.

The presented method provides a general procedure for the asymmetric syntheses of various N-aryl (R)-amino acid derivatives and for the asymmetric syntheses of dihydroquinoxalinones.

β-Alkoxyacrylates are efficient radical acceptors in intramolecular addition of O-stannyl ketyls. This cyclization reaction can be applied reiteratively to form fused oxacycles.

Novel 1H-pyrazolo[3,4-b]quinoxalines (flavazoles) 14, 15 and 1-aryl-3-quinoxalinyl-1,2,4-triazole 17 were synthesized from the ester 11 via various hydrazones 12, 13 and 16. In the antibacterial screening test of compounds 12–17, compound 14 showed a relatively high antibacterial activity, wherein the MIC value was 25 μg/ml against Bacillus licheniformis KTCC 21425 and Cellulomonas sp. and 50 μg/ml against Salmonella typhimurium KCTC 1925 and Flavobacterium devolans.

The pyridazino[3,4-b]quinoxaline 12 was synthesized by the cyclization of the α-arylhydrazonoacyl-hydrazide 11. The reaction of compound 12 with phosphoryl chloride gave pyridazino[3,4-b]quinoxaline 13, whose reactions with sodium azide or cyclic secondary amines provided pyridazino[3,4-b]quinoxalines 14,17 and 18, respectively. The acylhydrazide 15 was also cyclized to pyridazino[3,4-b]quinoxaline 16.

The reaction of the 6-chloro-2-(1-methyl-2-thiocarbamoylhydrazino)quinoxaline 4-oxides 3a-d with trifluoroacetic anhydride gave the 2-(N-aryl)trifluoroacetamido-8-chloro-4-methyl-4H-1,3,4-thiadiazino-[5,6-b]quinoxalines 7a-d, respectively, while the reflux of compounds 3a-c in N,N-dimethylformamide afforded the mesoionic triazolo[4,3-a]quinoxaline 4. Hydrolysis of compounds 7a-d with triethylamine/water provided the 2-arylamino-8-chloro-4-methyl-4H-1,3,4-thiadiazino[5,6-b)]quinoxalines 8a-d, respectively.

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with acetic anhydride resulted in the intramolecular cyclization to give 8-chloro-2,4-dimethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7a, while the reaction of compound 8 with acetic anhydride/pyridine or acetic anhydride/acetic acid afforded 3-(2,2-diacetyl-1-memymydrazmo)-7-chloro-2-oxo-1,2-dihydroquinoxaline 9, effecting no intramolecular cyclization. The reaction of 2-(2-acetyl-1-methylhydrazino)-6-chloroquinoxaline 4-oxide 10a or 6-chloro-2-(1-methyl-2-trifluoroacetylhydrazino)quinoxaline 4-oxide 10b with phosphoryl chloride provided compound 7a or 8-chloro-4-memyl-2-trifluoromethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7b, respectively. The reaction of compound 7b with phosphorus pentasulfide gave 7-chloro-3-(1-methyl-2-trifluoroacetylhydrazino)-2-thioxo-1,2-dihydroquinoxaline 11, whose dehydration with sulfuric acid in acetic acid afforded 8-chloro-4-methyl-2-trifluoromemyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 12.

Asymmetric lithiation-substitutions by n-BuLi/(−)-sparteine with the N-Boc-N-(3-halopropyl)allylamines 1−4 provide the N-Boc-2-alkenylpyrrolidines (S)-5, (S)-6, and (S)-7 in yields of 31−93% with enantiomeric ratios (ers) from 65:35 to 90:10. These reactions are shown to involve an initial asymmetric deprotonation, but the enantiodetermining step is a subsequent asymmetric cyclization under the influence of the chiral ligand. Extension to formation of a piperidine is illustrated by reaction of N-Boc-(4-chlorobutyl)cinnamylamine (9) to afford (S)-N-Boc-2-(trans-β-styryl)piperidine ((S)-10) in 68% yield with an enantiomeric ratio (er) of 84:16. Analogous reactions with epoxide ring openings of N-Boc-N-(oxaalkenyl)benzylamines 11 and 12 afford the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)pyrrolidine (13) in 67% yield with a diastereomeric ratio (dr) of 50:50 and ers of 97:3 and 95:5 and the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)piperidine (14) in 29% yield with a dr of 86:14 and ers of 81:19 and...

The synthesis of pyrrolidine or piperidine ring-fused 2-phenyl-azepino[5,4,3- cd ]indole derivatives ( 2 ) has been accomplished through the N -acyliminium ion cyclization of hydroxy- or alkoxylactams ( 5 ) derived from cyclic anhydrides or chiral hydroxy acids.

Aromatic aldehydes were easily converted to the corresponding ethers in methanol or ethanol using decaborane at r.t. under nitrogen in high yields.

A concise and efficient synthesis of tetracyclic azepino-indole derivatives 2 having a substituent at the angular position has been accomplished through an N-acyliminium ion cyclization. The coupling reaction of indol-3-yl-ethylamine 3 with 4-or 5-keto-acid 4 followed by cyclization reaction of the resulting tautomeric mixtures of keto-amide 5 and hydroxylactam 6 in refluxing formic acid provided 2.

Alkenes and alkynes were reduced to corresponding alkanes in methanol using decaborane (B10H14) in the presence of Pd/C as catalyst under nitrogen in high yields.

More than 99% of NO was directly decomposed into N2 and O2 without formation of N2O at space velocity of 45360 h−1 and apparent temperature of 280 °C over plasma-assisted Co3O4/Cu-ZSM-5 catalyst.

Novel D- and L-2′-azido-2′,3′-dideoxy-4′-thionucleosides were synthesized starting from L- and D-xylose via D- and L-4-thioarabitol derivative as key intermediates and evaluated for antiviral activity, respectively. When the final nucleosides were tested against HIV-1, HSV-1, HSV-2, and HCMV, they were found to be only active against HCMV without cytotoxicity up to 100 μg/ml.

The 4-anilinoquinazoline PD 153035 (1) is a potential antitumor agent which acts by inhibiting tyrosine kinase activity of epidermal growth factor receptor (EFGR) via competitive binding at the ATP site of enzyme. A series of cyclic analogues of PD 153035 bearing the 1,4-dioxane ring was prepared by reaction of 6-chloro derivative 5 with several aniline nucleophiles. These were evaluated for their ability to inhibit the EGFR kinase and the growth of primary human tumor cell cultures. All of the new 4-anilinoquinazolines exhibited less potency than PD 153035 against EGFR kinase. However, compounds 2b, 2c, 2e, 2g, and 2h showed higher inhibitory activities than PD 153035 against the growth of A431 tumor cell line. The compound 2b containing 3-chloroaniline ring was as potent as PD 153035 against EGFR kinase and showed about 5.4-fold better potency than PD153035 in the inhibition of growth of A431 cell line with good selectivity.

Novel d -2′-azido-2′,3′-dideoxyarabinofuranosyl-4′-thiopyrimidines and purines have been synthesized, starting from l -xylose via azidation at the 2′-position as a key step. Most of the final nucleosides exhibited toxicity-dependent anti-HIV-1 activity, among which d -α-adenine analogue 3h was found to be the most cytotoxic.