Synthesis of 2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3-((dimethylamino)methyl)camphor organocatalysts

In a stereo-divergent synthesis, three novel camphor-derived bifunctional thiourea organocatalysts 7-9 have been prepared in five steps starting from (+)-camphor. In addition, borneol-derived bifunctional thiourea organocatalysts 19/19' have been prepared in three steps from (1S)-(+)-camphorquinone. Novel organocatalysts 7-9, 19/19' have been evaluated in a model reaction of Michael addition of dimethyl malonate to trans-β-nitrostyrene with low to moderate enantioselectivities (20%-60% ee). Configuration of all novel compounds has been meticulously determined using nuclear magnetic resonance (NMR) techniques.     

Synthesis of New exo‐ and endo‐3,8‐Dihydro‐β‐santalols and Other Norbornyl‐Derived Alcohols

Several new and differently functionalized cis‐2,3‐dimethylnorbornane derivatives presenting diverse side‐chain lengths were prepared, the structures of which are related to the natural fragrance β‐santalol. In particular, exo‐ and endo‐3,8‐dihydro‐β‐santalols, with either (E) or (Z) C?C‐bond configuration on the side chain, were synthesized in seven steps and 21–24% overall yields. Several other exo‐ and endo‐norbornyl alcohols with shorter side chains were also prepared in high yields. The olfactory evaluation indicated woody, sandalwood, as well as fruity notes for some of the derivatives.     

The role of the C(2) configuration and methyl substitution on the catalytic activity of novel 2,3,3‐ and 2,7,7‐trimethyl‐substituted γ‐aminonorbornan‐2‐ols

A new set of optically active 2,3,3‐ and 2,7,7‐trimethyl‐substituted γ‐aminonorbornan‐2‐ols have been obtained from 2‐methylenenorbornane‐1‐carbonitriles derived from (+)‐camphor and (?)‐fenchone and probed as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde. This has allowed the study of the structural factors influencing the chirality transfer, such as variation of the relative configuration at C(2) and steric hindrance at C(2), C(3), and C(7) positions of norbornane, which result in the observance of the important role played by the gem‐dimethyl position in γ‐aminonorbornan‐2‐exo‐ols. An empirical rationalization of the obtained experimental results has been realized on the basis of energetically‐favored diastereomeric Noyori‐like transition states. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

Synthesis and Transformations of Novel L‐Phenylalanine Derived Pyrazolidin‐3‐ones

A simple and straightforward four‐step synthesis of novel diastereomeric L‐phenylalanine‐derived pyrazolidin‐3‐ones is described. The absolute configuration of the novel C(5) stereogenic centre has been unambiguously determined by single crystal X‐ray analysis and via chemical interconversions. A series of novel thiourea derived pyrazolidinones have been prepared and tested as potential organocatalysts. N(1) un‐substituted pyrazolidinones can be used for the construction of a novel type of bicyclic heterocycles and other selective derivatizations. Chirality 25:541–555, 2013. © 2013 Wiley Periodicals, Inc.     

Novel Route to Fe‐Based Cathode as an Efficient Bifunctional Catalysts for Rechargeable Zn–Air Battery

Efficient bifunctional oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) catalysts are of great importance for rechargeable metal–air batteries. Herein, FeN_x/C catalysts are synthesized by pyrolysis of thiourea and agarose containing α‐Fe₂O₃ nanoplate as Fe precursor, where α‐Fe₂O₃ nanoplate can prevent the aggregation of carbon sheets to effectively improve the specific surface area during the carbonization process. The FeN_x/C‐700‐20 catalyst displays excellent catalytic performance for both ORR and OER activity in alkaline conditions with more positive onset potential (1.1 V vs the reversible hydrogen electrode) and half‐wave potential, higher stability, and stronger methanol tolerance in alkaline solution, which are all superior to that of the commercial Pt/C catalyst. In this study, the detailed analyses demonstrate that the coexistence of Fe‐based species and high content of Fe‐N_x both play an important role for the catalytic activity. Furthermore, FeN_x/C‐700‐20 as cathode catalyst in Zn–air battery possesses higher charge–discharge stability and power density compared with that of commercial Pt/C catalyst, displaying great potential in practical implementation of for the rechargeable energy devices.     

Synthesis of enantiomers of exo‐2‐norbornyl‐N‐n‐butylcarbamate and endo‐2‐norbornyl‐N‐n‐butylcarbamate for stereoselective inhibition of acetylcholinesterase

The acetylcholinesterase inhibition by enantiomers of exo‐ and endo‐2‐norbornyl‐N‐n‐butylcarbamates shows high stereoselelectivity. For the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐exo‐2‐norbornyl‐N‐n‐butylcarbamates, the R‐enantiomer is more potent than the S‐enantiomer. But, for the acetylcholinesterase inhibitions by (R)‐(+)‐ and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates, the S‐enantiomer is more potent than the R‐enantiomer. Optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norbornyl‐N‐n‐butylcarbamates are synthesized from condensations of optically pure (R)‐(+)‐exo‐, (S)‐(?)‐exo‐, (R)‐(+)‐endo‐, and (S)‐(?)‐endo‐2‐norborneols with n‐butyl isocyanate, respectively. Optically pure norborneols are obtained from kinetic resolutions of their racemic esters by lipase catalysis in organic solvent. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Synthesis and chiroptical properties of organometallic complexes of helicenic N‐heterocyclic carbenes

Novel [4, 6]helicenes ( 4a,b ) bearing a fused imidazolium unit have been prepared from [4, 6]helicene‐2,3‐di‐n‐propyl‐amines 3a,b . The in situ formation of N‐heterocyclic carbene (NHC) derivatives followed by their complexation to iridium(I) or rhodium(I) gave access to complexes 1a , 1′a , and 1b , containing mono‐coordinated helicene‐NHC, chloro and COD (COD = 1,5‐cyclooctadiene) ligands. Ir and Rh complexes 1a and 1′a were characterized by X‐ray crystallography. HPLC and NMR analyses showed that Ir(I) complex 1b existed as a mixture of two diastereomeric complexes corresponding to enantiomeric pairs M‐(?)/P‐(+)‐ 1b ¹ and M‐(?)/P‐(+)‐ 1b ² which differ by the position of COD through space. The chiroptical properties (electronic circular dichroism and optical rotation) of the four stereoisomers were measured. These complexes were also tested as catalysts in a transfer hydrogenation reaction.     

A Simple Method for Resolution of Endo‐/Exo‐Monoesters of Trans‐Norborn‐5‐Ene‐2,3‐Dicarboxylic Acids Into Their Enantiomers

Separation of optical isomers obtainable from trans‐norborn‐5‐ene‐2,3‐dicarboxylic acid methyl and tert‐butyl monoesters was performed by crystallization of the respective salts prepared with (R)‐ and (S)‐1‐phenylethylamine. Starting from racemic endo‐monomethyl ester of trans‐norborn‐5‐ene‐2,3‐dicarboxylic acid, prepared by partial hydrolysis of the cyclopentadiene‐dimethyl fumarate adduct, the corresponding (2R,3R)‐endo‐monoester was isolated in 97% enantiomeric excess (ee) yield after seven repeated crystallizations from tetrachloromethane. Starting from exo‐mono‐tert‐butyl ester of the same acid, prepared by alcoholysis of the cyclopentadiene‐maleic anhydride adduct followed by isomerization, (2R,3R)‐exo‐monoester was isolated in >98% ee yield after four repeated crystallizations from ethanol. Crystallization of the acids from the mother liquor containing (S)‐1‐phenylethylamine yielded products with inverse stereochemical configuration. Chirality 27:151–155, 2015. © 2014 Wiley Periodicals, Inc.     

Novel Chiral Bifunctional L‐Thiazoline‐Thiourea Derivatives: Design and Application in Enantioselective Michael Reactions

Several novel chiral bifunctional L‐thiazoline‐thiourea derivatives were easily synthesized from commercially available L‐cysteine in high yield. These catalysts were subsequently applied to the enantioselective Michael addition of acetylacetone to β‐nitrostyrenes. The products with S configuration were obtained in 98% enantiomeric excess (ee) when the L‐thiazoline‐thiourea derivatives were used. A plausible transition state model is proposed to explain the observed enantioselectivities. Chirality 27:979–988, 2015. © 2015 Wiley Periodicals, Inc.     

Homochiral bifunctional L‐prolinamide‐ and L‐bis‐prolinamide‐catalyzed asymmetric aldol reactions performed in wet solvent‐free conditions

In this study, the novel bifunctional homochiral thiourea‐L‐prolinamides 1–4 , tertiary amino‐L‐prolinamide 5 , and bis‐L‐prolinamides 6 and 7 were prepared from enantiomerically pure (11R,12R)‐11,12‐diamino‐9,10‐dihydro‐9,10‐ethanoanthracene 8 and (11S,12S)‐11,12‐diamino‐9,10‐dihydro‐9,10‐ethanoanthracene ent‐8 . Highly enantioselective and diastereoselective aldolic intermolecular reactions (up to 95% enantiomeric excess, 93:7 anti/syn) between aliphatic ketones (20 equiv) and a range of aromatic aldehydes (1 equiv) were successfully carried out in the presence of water (10 equiv) and monochloroacetic acid (10 mol%), solvent‐free conditions, at room temperature over 24 h using organocatalysts 1–7 (5 mol%). Stereoselective induction using density functional theory–based methods was consistent with the experimental data.     

Synthesis and Structural Characterization of Novel Camphor-derived Amines

Two novel 4‐substituted camphidine derivatives 10a , b have been prepared from (+)‐camphor ( 1 ) in five steps, the Beckmann rearrangement being the bottleneck of the synthesis. Isoborneol derivative 5b , formed as a side product during the hydrogenation of arylidene ketone 3b , under Beckmann rearrangement conditions yielded interesting novel rearrangement products 11 and 12 . (1S)‐(+)‐Camphorquinone ( 13 ) was transformed into diamines 15 and 16 in two steps, the former being cyclized into an imidazoline salt 17 , an N‐heterocyclic carbene precursor. The structures of all novel compounds have been meticulously characterized using NMR techniques and/or single crystal X‐ray analysis. Chirality 24:778–788, 2012. © 2012 Wiley Periodicals, Inc.     

Thuja occidentalis: identification of volatiles and electroantennographic response by the invasive cedar bark beetle,Phloeosinus aubei

Recently, the distribution of the Mediterranean cedar bark beetle, Phloeosinus aubei Perris (Coleoptera: Scolytidae), has expanded to Central Europe. Reported mostly on cypress in the Mediterranean area, potential host plants in the invaded range include other scale‐leafed conifers, such as cultivars of arborvitae, Thuja occidentalis L. To reveal potential kairomonal cues for P. aubei, volatiles of T. occidentalis were collected and analysed by gas chromatography with electroantennographic detection (GC‐EAD). Assignments of chemical structures of antennally active components were carried out by gas chromatography linked to mass spectrometry (GC‐MS) using authentic reference samples. Antennal responses to synthetic samples of the identified compounds were studied by electroantennography (EAG), with antennae of female and male P. aubei. GC‐EAD analysis of head space volatiles of T. occidentalis revealed 22 antennally active compounds, of which 21 were identified. The most abundant components were α‐ and β‐thujone, fenchone, camphor, terpinen‐4‐ol, bornyl acetate and α‐terpinyl acetate, all of which are oxygenated monoterpenes. When EAG activities of synthetic samples were compared, the most intensive responses from female antennae were elicited by a mixture of α‐ and β‐thujone, followed by (–)‐terpinen‐4‐ol, (+)‐camphor, cis‐4‐thujanol, (+)‐sabina ketone, (+)‐terpinen‐4‐ol, isopulegone, (–)‐fenchone, borneol, (3Z)‐hexen‐1‐ol, (–)‐1‐octen‐3‐ol and (+)‐sulcatol. Male antennae responded the most to (–)‐terpinen‐4‐ol and cis‐4‐thujanol followed by the mixture of α‐ and β‐thujone. The next highest responses were elicited by (+)‐camphor, borneol, (+)‐terpinen‐4‐ol, (+)‐sulcatol and (+)‐sabina ketone. Striking differences were found between responses to the enantiomers of fenchone, sulcatol and 1‐octen‐3‐ol, whereas responses to the enantiomers of terpinen‐4‐ol did not differ significantly from each other. Several antennally active volatiles of T. occidentalis have also been reported from cypress and various other members of the Cupressaceae, suggesting that the sensory apparatus of P. aubei may recognize the shared components, which may enable rapid adaptation to new hosts in the invaded areas.     

Molecular dynamics of the P450cam–Pdx complex reveals complex stability and novel interface contacts

Cytochrome P450cam catalyzes the stereo and regiospecific hydroxylation of camphor to 5‐exo‐hydroxylcamphor. The two electrons for the oxidation of camphor are provided by putidaredoxin (Pdx), a Fe₂S₂ containing protein. Two recent crystal structures of the P450cam–Pdx complex, one solved with the aid of covalent cross‐linking and one without, have provided a structural picture of the redox partner interaction. To study the stability of the complex structure and the minor differences between the recent crystal structures, a 100 nanosecond molecular dynamics (MD) simulation of the cross‐linked structure, mutated in silico to wild type and the linker molecule removed, was performed. The complex was stable over the course of the simulation though conformational changes including the movement of the C helix of P450cam further toward Pdx allowed for the formation of a number of new contacts at the complex interface that remained stable throughout the simulation. While several minor crystal contacts were lost in the simulation, all major contacts that had been experimentally studied previously were maintained. The equilibrated MD structure contained a mixture of contacts resembling both the cross‐linked and noncovalent structures and the newly identified interactions. Finally, the reformation of the P450cam Asp251–Arg186 ion pair in the MD simulation mirrors the ion pair observed in the more promiscuous CYP101D1 and suggests that the Asp251–Arg186 ion pair may be important.     

Enantiomeric resolution of asymmetric glycol by a lipase‐catalyzed transesterification reaction

The lipase catalyzed enantiomeric resolution of syn‐glycol was carried out to confirm the sector method, which can determine the absolute configuration of anti‐ and syn‐glycol from the ¹H‐NMR spectra of bis‐2‐methoxy‐2‐trifluoromethyl‐2‐phenylacetic acid (MTPA) esters. The lipase catalyzed transesterification reaction was most reactive at the C2 position (C2–OH) of (2R;3R)‐2,3‐octanediol. Both (2S;3S)‐ and (2R;3R)‐2,3‐octanediol were prepared using lipase. The ¹H‐NMR spectra of their bis‐(R)‐MTPA esters agreed well with those prepared previously via mono‐(R)‐MTPA esters. The result suggests the retention of the Mosher plane in MTPA esters possessing a hydroxyl group at the β position. The reaction rate and the stereoselectivity decreased at C2–OH with the addition of 18‐crown‐6. Chirality 11:338–342, 1999. © 1999 Wiley‐Liss, Inc.     

Design,synthesis and application of chiral tetraoxacalix[2]arene[2]triazine‐based organocatalysts in asymmetric Michael addition reactions

A novel type of oxacalix[2]arene[2]triazine‐based organocatalysts for asymmetric Michael reactions are reported for the first time. Chiral subunits were attached to the heteroatom‐bridged calixaromatic platform by a reaction of (R)‐ and (S)‐1‐aminotetraline with tetraoxacalix[2]arene[2]triazine in both enantiomeric forms. To evaluate the catalytic efficiency of the novel organocatalysts, isobutyraldehyde reacted with various substituted and unsubstituted aromatic trans‐β‐nitrostyrenes in tetrahydrofuran (THF), leading to Michael adducts in excellent yields and enantioselectivites (up to 97% yield and 99% ee).     

Novel Phenyl‐1‐benzoxepinols from Butcher's Broom (Rusci rhizoma)

Two novel compounds, (3S)‐2,3‐dihydro‐3‐(4‐hydroxyphenyl)‐1‐benzoxepin‐8‐ol ( 1 ; ruscozepine A) and (3S)‐2,3‐dihydro‐3‐(4‐hydroxyphenyl)‐8‐methoxy‐1‐benzoxepin‐7‐ol ( 2 ; ruscozepine B) were isolated from butcher's broom (Rusci rhizoma) together with a biosynthetically possible phenylethanoid precursor, hydroxytyrosol ( 3 ). The structures were elucidated by spectroscopic methods such as 1D‐ and 2D‐NMR (COSY, HSQC, HMBC, ROESY), and HR‐EI‐MS experiments. The absolute configuration of the ruscozepines was determined by electronic circular dichroism.     

Various Polar Tripeptides as Asymmetric Organocatalyst in Direct Aldol Reactions in Aqueous Media

A series of tripeptide organocatalysts containing a secondary amine group and two amino acids with polar side chain units were developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4‐nitrobenzaldehyde and cyclohexanone. The effectiveness of short polar peptides as asymmetric catalysts in aldol reactions to attain high yields of enantio‐ and diastereoselective isomers were investigated. In a comparison, glutamic acid and histidine produced higher % ee and yields when they were applied as the second amino acid in short trimeric peptides. These short polar peptides were found to be efficient organocatalysts for the asymmetric aldol addition reaction in aqueous media. Chirality 25:726–734, 2013. © 2013 Wiley Periodicals, Inc     

Pyrrole Derivatives and Diterpene Alkaloids from the South China Sea Sponge Agelas nakamurai

Two pairs of new non‐brominated racematic pyrrole derivatives, (±)‐nakamurine D ( 1 ) and (±)‐nakamurine E ( 2 ), two new diterpene alkaloids, isoagelasine C ( 16 ) and isoagelasidine B ( 21 ), together with 13 known pyrrole derivatives ((±)‐ 3  –  15 ), five known diterpene alkaloids ( 17  –  20 , 22 ) were isolated from the South China Sea sponge Agelas nakamurai . The racemic mixtures, compounds 1  –  4 , were resolved into four pairs of enantiomers, (+)‐ 1 and (?)‐ 1 , (+)‐ 2 and (?)‐ 2 , (+)‐ 3 and (?)‐ 3 , and (+)‐ 4 and (?)‐ 4 , by chiral HPLC . The structures and absolute configurations were elucidated on the basis of comprehensive spectroscopic analyses, quantum chemical calculations, quantitative measurements of molar rotations, application of van't Hoff 's principle of optical superposition, and comparison with the literature data. The NMR and MS data of compound 3 are reported for the first time, as the structure was listed in SciFinder Scholar with no associated reference. These non‐brominated pyrrole derivatives were found in this species for the first time. Compound 18 showed valuable cytotoxicities against HL ‐60, K562, and HCT ‐116 cell lines with IC ₅₀ values of 12.4, 16.0, and 19.8 μm , respectively. Compounds 16  –  19 , 21 , and 22 showed potent antifungal activities against Candida albicans with MIC values ranging from 0.59 to 4.69 μg/ml. Compounds 16  –  19 exhibited moderate antibacterial activities against Proteusbacillus vulgaris (MIC values ranging from 9.38 to 18.75 μg/ml).     

Synthesis and nootropic activity of some 2,3-dihydro-1H-isoindol-1-one derivatives structurally related with piracetam

Three 2,3‐dihydro‐1H‐isoindol‐1‐ones structurally related with piracetam (=2‐oxopyrrolidine‐1‐acetamide) have been synthesized and tested for their nootropic effects in the passive avoidance test in mice. Compounds (RS)‐ 2 , (R,R)‐ 3 , and (R,S)‐ 3 were obtained in good yields in only two steps starting from methyl dl ‐phthaloylalanine. Compound (RS)‐ 2 exhibited nootropic activity at lower doses than piracetam, used as reference drug, but it showed lower efficacy. Whereas diastereoisomers (R,R)‐ 3 and (R,S)‐ 3 were as potent as piracetam to revert amnesia induced by scopolamine, (R,S)‐ 3 showed lower efficacy than (R,R)‐ 3 . Only (R,R)‐ 3 showed myorelaxant effect at doses of 10 and 30 mg/kg; other compounds did not exhibit any anticonvulsant, sedative, myorelaxant, or impaired motor‐coordination effect in mice. These synthesized 2,3‐dihydro‐1H‐isoindol‐1‐one derivatives constitute a new kind of nootropic compounds.     

Chemical Diversity in the Genus Alpinia (Zingiberaceae): Comparative Composition of Four Alpinia Species Grown in Northern India

The essential‐oil compositions of leaves, flowers, and rhizomes of Alpinia galanga (L.) Willd ., Alpinia calcarata Rosc ., Alpinia speciosa K. Schum. , and Alpinia allughas Rosc . were examined and compared by capillary GC and GC/MS. Monoterpenoids were the major oil constituents identified. 1,8‐Cineole, α‐terpineol, (E)‐methyl cinnamate, camphor, terpinen‐4‐ol, and α‐ and β‐pinenes were the major constituents commonly distributed in leaf and flower essential oils. The presence of endo‐fenchyl acetate, exo‐fenchyl acetate, and endo‐fenchol was the unique feature of rhizome essential oils of A. galanga, A. calcarata, and A. speciosa. On contrary, the rhizome oil of A. allughas was dominated by β‐pinene. Significant qualitative and quantitative variations were observed in essential‐oil compositions of different parts of Alpinia species growing in subtemperate and subtropical regions of Northern India. Cluster analysis was performed to find similarities and differences in essential‐oil compositions based on representative molecular skeletons. Monoterpenoids, viz., 1,8‐cineole, terpinen‐4‐ol, camphor, pinenes, (E)‐methyl cinnamate, and fenchyl derivatives, were used as chemotaxonomic markers.