Highly enantioselective synthesis of α,α-dialkylmalonates by phase-transfer catalytic desymmetrization.

A novel enantioselective synthetic method for the construction of a quaternary carbon center from malonates via phase-transfer catalytic (PTC) alkylation has been developed. The asymmetric α-alkylation of diphenylmethyl tert-butyl α-alkylmalonates with alkylating agents under phase-transfer catalysis conditions (aq 50% KOH, toluene, 0 °C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (8) as PTC catalyst afforded the corresponding α,α-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 97% ee) which could be readily converted to versatile chiral intermediates. Notably, the direct double α-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding α,α-dialkylmalonates without loss of enantioselectivity. The synthetic potential of this method has been demonstrated by the preparation of α,α-dialkylamino acid and oxindole systems.

An enantioselective synthesis of (+)-polyoxamic acid via phase-transfer catalytic conjugate addition and asymmetric dihydroxylation.

A new enantioselective synthetic method of (+)-polyoxamic acid is reported. (+)-Polyoxamic acid could be obtained in 7 steps with 46% overall yield from diphenylmethyl-glycineimine tert-butyl ester via an enantioselective phase-transfer conjugate addition (99% yield, 96% ee) and an asymmetric dihydroxylation (98% yield, 94% de) as the key reactions.

Synthesis of (-)-paroxetine via enantioselective phase-transfer catalytic monoalkylation of malonamide ester.

A new enantioselective synthetic method of (-)-paroxetine is reported. (-)-Paroxetine could be obtained in 15 steps (95% ee and 9.1% overall yield) from N,N-bis(p-methoxyphenyl)malonamide tert-butyl ester via the enantioselective phase-transfer catalytic alkylation and the diastereoselective Michael addition as the key steps.

Cinchona-based phase-transfer catalysts for asymmetric synthesis.

Phase-transfer catalysis is one of the most useful methodologies for practical syntheses given its operational simplicity and mild reaction conditions that enable its application in industrial processes. Cinchona alkaloids have been a popular, natural source of practical organocatalysts due largely to their excellent commercial availability and low cost. Since the first Cinchona alkaloid-derived phase-transfer catalysts was disclosed in 1981, diverse generations of Cinchona-derived phase-transfer catalysts have been developed and successfully applied to various asymmetric syntheses. In this feature article, we describe the generation of Cinchona-derived chiral phase-transfer catalysts according to the development stages and our efforts toward the design of polymeric Cinchona phase-transfer catalysts, the effects of the electronic functional group incorporated in the catalysts, and their application in asymmetric organic reactions.

Asiatic acid derivatives protect primary cultures of rat hepatocytes against carbon tetrachloride-induced injury via the cellular antioxidant system.

We attempted to elucidate the hepatoprotective mechanism of two asiatic acid (AS) derivatives, 3beta,23-dihydroxyurs-2-oxo-12-ene-28-oic acid (AS-10) and 3beta,23-dihydroxyurs-12-ene-28-oic acid (AS-14), which exhibited significant protective activity against carbon tetrachloride (CCl4)-induced hepatotoxicity in primary cultures of rat hepatocytes. Our findings showed that AS-10 and AS-14 preserved the level of glutathione and the activities of antioxidant enzymes such as glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase. In addition, these compounds ameliorated lipid peroxidation, as demonstrated by a reduction in the production of malondialdehyde. Furthermore, AS-10 and AS-14 did not restore the reduced total GSH level by BSO, indicating that the hepatoprotective activities of these compounds may be involved, in part, by regulating GSH synthesis. From these results, we suggest that both AS-10 and AS-14 exerted their hepatoprotective activities against CCl4-induced injury by preserving the cellular antioxidative defense system.

Highly enantioselective synthesis of (S)-alpha-alkyl-alpha,beta-diaminopropionic acids via asymmetric phase-transfer catalytic alkylation of 2-phenyl-2-imidazoline-4-carboxylic acid tert-butyl esters.

An efficient enantioselective synthetic method for (S)-alpha-alkyl-alpha,beta-diaminopropionic acid is reported. The asymmetric phase-transfer catalytic alkylation of N(1)-Boc-2-phenyl-2-imidazoline-4-carboxylic acid tert -butyl ester in the presence of chiral quaternary ammonium catalyst gave the corresponding alkylated products (93-98% ee) which could be transformed to enantioenriched alpha-alkyl-alpha,beta-diaminopropionic acids.

The highly enantioselective phase-transfer catalytic mono-alkylation of malonamic esters.

The phase-transfer catalytic alkylation of N,N-dialkylmalonamic tert-butyl esters in the presence of 1 mol% of (S,S)-3,4,5-trifluorophenyl-NAS bromide afforded highly enantioselective (S)-mono-alpha-alkylated products (up to 96% ee), which could be readily converted into versatile chiral building blocks without loss of chirality.

Phase-transfer catalytic aza-Michael addition of tert-butyl benzyloxycarbamate to electron-deficient olefins.

A highly efficient phase-transfer catalytic aza-Michael addition of tert-butyl benzyloxycarbamate to a wide range of electron-deficient olefins is presented (90-99%).

Enantioselective synthesis of (-)-cis-clavicipitic acid.

An enantioselective synthetic method for (-)-cis-clavicipitic acid (1) was reported. 1 was obtained in 10 steps (99% ee and 20% overall yield) from 1H-indole-3-carboxylic acid methyl ester (9) via asymmetric phase-transfer catalytic alkylation and diastereoselective Pd(II)-catalyzed intramolecular aminocyclization as key steps.

Enantioselective synthesis of (R)- and (S)-alpha-alkylcysteines via phase-transfer catalytic alkylation.

We reported efficient enantioselective synthetic methodologies for (R)-alpha-alkylcysteines and (S)-alpha-alkylcysteines. The phase-transfer catalytic alkylation of 2-phenyl-2-thiazoline-4-carboxylic acid tert-butyl ester and 2-o-biphenyl-2-thiazoline-4-carboxylic acid tert-butyl ester, in the presence of chiral catalysts (1 or 2), gave the corresponding alkylated products, which could be hydrolyzed to provide (R)-alpha-alkylcysteines (67->99% ee) and (S)-alpha-alkylcysteines (66-88% ee), respectively.

Total synthesis of (+)-hygrine via asymmetric phase-transfer catalytic alkylation.

The first enantioselective synthesis of (+)-hygrine (1) is reported. 1 was obtained in 12 steps with 29% overall yield and 97% ee via asymmetric phase-transfer catalytic alkylation and ring-closing metathesis as key steps. The absolute configuration of (+)-hygrine could be directly confirmed as R.

Highly enantioselective synthesis of (2S)-alpha-(hydroxymethyl)-glutamic acid by the catalytic Michael addition of 2-naphthalen-1-yl-2-oxazoline-4-carboxylic acid tert-butyl ester.

[reaction: see text]. Highly enantioselective synthesis of a potent metabotropic receptor ligand, (2S)-alpha-(hydroxymethyl)-glutamic acid (2, HMG) was accomplished by the catalytic Michael addition of 2-naphthalen-1-yl-2-oxazoline-4-carboxylic acid tert-butyl ester (3b), using the phosphazene base, BEMP, in CH(2)Cl(2) at -60 degrees C in the presence of (S)-binaphthyl quaternary ammonium salt 4.

Enantioselective synthetic method for alpha-alkylserine via phase-transfer catalytic alkylation of 2-phenyl-2-oxazoline-4- carbonylcamphorsultam.

[reaction: see text] An enantioselective synthetic method for alpha-alkylserines by the phase-transfer catalytic alkylation of 2-phenyl-2-oxazoline-4-carbonylcamphorsultam (4a) was developed. The phase-transfer catalytic alpha-alkylation of 4a using P2-Et at -78 degrees C gave alpha-alkylation (75 to approximately 99%, 90 to approximately 97% de), which could be easily hydrolyzed to alpha-alkylserines.

Highly enantioselective synthesis of (R)-alpha-alkylserines via phase-transfer catalytic alkylation of o-biphenyl-2-oxazoline-4-carboxylic acid tert-butyl ester using cinchona-derived catalysts.

[reaction: see text] A highly enantioselective synthetic method for (R)-alpha-alkylserines was developed by the phase-transfer catalytic alkylation of o-biphenyl-2-oxazoline-4-carboxylic acid tert-butyl ester (4i) using cinchona-derived phase-transfer catalyst N(1)-(9-anthracenylmethyl)-O(9)-allyl-dihydrocinchonidinium bromide (up to 96% ee).

Evidence of the electronic factor for the highly enantioselective catalytic efficiency of Cinchona-derived phase-transfer catalysts.

[structure: see text] The Cinchona alkaloid-derived quaternary ammonium salts containing 2'-N-oxypyridine and 2'-cyanobenzene moieties were prepared and evaluated as phase-transfer catalysts in the enantioselective alkylation of glycine imine ester 1. The N-oxypyridine and cyanobenzene moieties might play an important role to form a rigid conformation by coordinating with H(2)O via hydrogen bonding leading to high enantioselectivity (97 approximately >99% ee), which provides evidence of an electronic factor for the high enantioselective catalytic efficiency in phase-transfer alkylation.

Highly enantioselective phase-transfer catalytic alkylation in the preparation of non-natural alpha-amino acids via solid phase synthesis using aldimine linker.

A new Merrifield-resin-derived glycinimine tert-butyl ester (9) was prepared and applied to the enantioselective synthesis of non-natural alpha-amino acids. High enantioselectivities (86 to >99% ee) were accomplished by employing the aldimine linker under phase-transfer alkylation conditions, using 50% aqueous CsOH in toluene/chloroform (7:3) at 0 degrees C in the presence of N-(9-anthracenylmethyl)-O(9)-allylcinchonidium bromide (10 mol %).

Biarylcarboxybenzamide derivatives as potent vanilloid receptor (VR1) antagonistic ligands.

Seventeen biarylcarboxybenzamide derivatives were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor (VR1) in rat DRG neurons. The replacement of the piperazine moiety of the lead compound 1 with phenyl ring showed quite enhanced antagonistic activity. Among the prepared derivatives, N-(4-tert-butylphenyl)-4-pyridine-2-yl-benzamide (2, IC(50)=31 nM) and N-(4-tert-butylphenyl)-4-(3-methylpyridine-2-yl)benzamide (3g, IC(50)=31 nM), showed 5-fold higher antagonistic activity than 1 in (45)Ca(2+)-influx assay.

Asiatic acid derivatives enhance cognitive performance partly by improving acetylcholine synthesis.

Thirty-six semi-synthesized derivatives of asiatic acid were examined to determine if they had cognitive-enhancing activity in a passive avoidance test. Among the compounds tested, AS-2, AS-2-9-006 and AS-9-006 significantly alleviated scopolamine-induced memory impairment at doses of 1 and 10 mg kg(-1). Furthermore, AS-2 and AS-2-9-006 (1 mg kg(-1) administered four times daily) enhanced cognitive performance as determined in a water maze test. These three asiatic acid derivatives did not show any significant effect on the learning process in active avoidance tests. AS-2, AS-2-9-006 and AS-9-006 enhanced cholineacetyltransferase activity in a cholinergic neuroblastoma cell line, S-20Y, in-vitro. Therefore, AS-2, AS-2-9-006 and AS-9-006 may have therapeutic value in alleviating certain memory impairment observed in dementia.