Ring‐Opening Reactions of 3‐Aryl‐1‐benzylaziridine‐2‐carboxylates and Application to the Asymmetric Synthesis of an Amphetamine‐Type Compound

Nucleophilic ring‐opening reactions of 3‐aryl‐1‐benzylaziridine‐2‐carboxylates were examined by using O‐nucleophiles and aromatic C‐nucleophiles. The stereospecificity was found to depend on substrates and conditions used. Configuration inversion at C(3) was observed with O‐nucleophiles as a major reaction path in the ring‐opening reactions of aziridines carrying an electron‐poor aromatic moiety, whereas mixtures containing preferentially the syn‐diastereoisomer were generally obtained when electron‐rich aziridines were used (Tables 1–3). In the reactions of electron‐rich aziridines with C‐nucleophiles, S_N2 reactions yielding anti‐type products were observed (Table 4). Reductive ring‐opening reaction by catalytic hydrogenation of (+)‐trans‐(2S,3R)‐3‐(1,3‐benzodioxol‐5‐yl)aziridine‐2‐carboxylate (+)‐trans‐ 3c afforded the corresponding α‐amino acid derivative, which was smoothly transformed into (+)‐tert‐butyl [(1R)‐2‐(1,3‐benzodioxol‐5‐yl)‐1‐methylethyl]carbamate((+)‐ 14 ) with high retention of optical purity (Scheme 6).     

An Efficient Synthesis of Optically Active trans‐(3R,4R)‐3‐Acetoxy‐4‐aryl‐1‐(chrysen‐6‐yl)azetidin‐2‐ones Using (+)‐Car‐3‐ene as a Chiral Auxiliary

An efficient enantioselective synthesis of 3‐acetoxy trans‐β‐lactams 7a and 7b via [2+2] cycloaddition reactions of imines 4a and 4b , derived from a polycyclic aromatic amine and bicyclic chiral acid obtained from (+)‐car‐3‐ene, is described. The cycloaddition was found to be highly enantioselective, producing only trans‐(3R,4R)‐N‐azetidin‐2‐one in very good yields. This is the first report of the synthesis of enantiomerically pure trans‐β‐lactams 7a and 7b with a polycyclic aromatic substituent at N(1) of the azetidin ring.     

Analogues of α‐Campholenal (= (1R)‐2,2,3‐Trimethylcyclopent‐3‐ene‐1‐acetaldehyde) as Building Blocks for (+)‐β‐Necrodol (= (1S,3S)‐2,2,3‐Trimethyl‐4‐methylenecyclopentanemethanol) and Sandalwood‐like Alcohols

To complete our panorama in structure–activity relationships (SARs) of sandalwood‐like alcohols derived from analogues of α‐campholenal (= (1R)‐2,2,3‐trimethylcyclopent‐3‐ene‐1‐acetaldehyde), we isomerized the epoxy‐isopropyl‐apopinene (?)‐ 2d to the corresponding unreported α‐campholenal analogue (+)‐ 4d (Scheme 1). Derived from the known 3‐demethyl‐α‐campholenal (+)‐ 4a , we prepared the saturated analogue (+)‐ 5a by hydrogenation, while the heterocyclic aldehyde (+)‐ 5b was obtained via a Bayer‐Villiger reaction from the known methyl ketone (+)‐ 6 . Oxidative hydroboration of the known α‐campholenal acetal (?)‐ 8b allowed, after subsequent oxidation of alcohol (+)‐ 9b to ketone (+)‐ 10 , and appropriate alkyl Grignard reaction, access to the 3,4‐disubstituted analogues (+)‐ 4f,g following dehydration and deprotection. (Scheme 2). Epoxidation of either (+)‐ 4b or its methyl ketone (+)‐ 4h , afforded stereoselectively the trans‐epoxy derivatives 11a,b , while the minor cis‐stereoisomer (+)‐ 12a was isolated by chromatography (trans/cis of the epoxy moiety relative to the C₂ or C₃ side chain). Alternatively, the corresponding trans‐epoxy alcohol or acetate 13a,b was obtained either by reduction/esterification from trans‐epoxy aldehyde (+)‐ 11a or by stereoselective epoxidation of the α‐campholenol (+)‐ 15a or of its acetate (?)‐ 15b , respectively. Their cis‐analogues were prepared starting from (+)‐ 12a . Either (+)‐ 4h or (?)‐ 11b , was submitted to a Bayer‐Villiger oxidation to afford acetate (?)‐ 16a . Since isomerizations of (?)‐ 16 lead preferentially to β‐campholene isomers, we followed a known procedure for the isomerization of (?)‐epoxyverbenone (?)‐ 2e to the norcampholenal analogue (+)‐ 19a . Reduction and subsequent protection afforded the silyl ether (?)‐ 19c , which was stereoselectively hydroborated under oxidative condition to afford the secondary alcohol (+)‐ 20c . Further oxidation and epimerization furnished the trans‐ketone (?)‐ 17a , a known intermediate of either (+)‐β‐necrodol (= (+)‐(1S,3S)‐2,2,3‐trimethyl‐4‐methylenecyclopentanemethanol; 17c ) or (+)‐(Z)‐lancifolol (= (1S,3R,4Z)‐2,2,3‐trimethyl‐4‐(4‐methylpent‐3‐enylidene)cyclopentanemethanol). Finally, hydrogenation of (+)‐ 4b gave the saturated cis‐aldehyde (+)‐ 21 , readily reduced to its corresponding alcohol (+)‐ 22a . Similarly, hydrogenation of β‐campholenol (= 2,3,3‐trimethylcyclopent‐1‐ene‐1‐ethanol) gave access via the cis‐alcohol rac‐ 23a , to the cis‐aldehyde rac‐ 24 .     

An Efficient Stereoselective Total Synthesis of Bioactive (3R,5R)‐1‐(4‐Hydroxyphenyl)‐7‐phenylheptane‐3,5‐diol via Asymmetric Aldol Reaction

An efficient stereoselective total synthesis of (3R,5R)‐1‐(4‐hydroxyphenyl)‐7‐phenylheptane‐3,5‐diol ( 1 ) is reported based on the Mukaiyama aldol reaction. The total synthesis of compound 1 was accomplished with 30% overall yield in simple eight steps from commercially available trans‐cinnamaldehyde.     

1‐Aminoindan‐2‐ol,a Suitable Ligand for the Synthesis of Chiral,Intramolecularly Stabilized Compounds of Aluminum,Gallium, and Indium

The reactions of enantiomerically pure (1R, 2S)‐(+)‐cis‐1‐aminoindan‐2‐ol, (1S, 2R)‐(‐)‐cis‐1‐aminoindan‐2‐ol, and racemic trans‐1‐aminoindan‐2‐ol with trimethylaluminum, ‐gallium, and ‐indium produce the intramolecularly stabilized, enantiomerically pure dimethylmetal‐1‐amino‐2‐indanolates (1R, 2S)‐(+)‐cis‐Me₂AlO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 1 ), (1S, 2R)‐(‐)‐cis‐Me₂AlO‐2C*HC₇H₆‐1‐C*HNH₂ ( 2 ), (1R, 2S)‐(+)‐cis‐Me₂GaO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 3 ), (1R, 2S)‐(+)‐cis‐Me₂InO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 4 ), (1S, 2R)‐(‐)‐cis‐Me₂InO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 5 ), and racemic (+/‐)‐trans‐Me₂InO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 6 ). The compounds were characterized by ¹H NMR, ¹³C NMR, ²⁷Al NMR and mass spectra as well as 1 and 3 to 6 by determination of their crystal and molecular structures. The dynamic dissociation/association behavior of the coordinative metal‐nitrogen bond was studied by low temperature ¹H NMR spectroscopy.     

Theoretical investigation into the coordination of R‐/S‐asymmetric uranyl–salophens containing six‐membered ring lactam with cis−/trans‐cyclohexylamines

A six‐membered ring lactam derivative was introduced in a parallel manner into uranyl–salophens with R/S configuration (R‐/S‐AUSRLs), which were used as receptors to coordinate with guests of cis?/trans‐methylcyclohexylamines (cis?/trans‐MCHAs). Using density functional theory calculations at the B3LYP/6‐311G** level and RECP, an insight into the coordination complexes of the R‐/S‐AUSRLs with cis?/trans‐MCHAs was obtained. The results showed that the U atoms of receptors could coordinate with the N atoms of four kinds of cis?/trans‐1,2 or ? 1,4 guests, but the two kinds of cis?/trans‐1,3 guests could not be converged by the same method in the process of structural optimization due to steric hindrance, and thus the cis?/trans‐1,3 guests could not be coordinated with the R‐/S‐AUSRLs. The mode of coordination of the R‐/S‐AUSRLs with the guests displayed a significant difference. And the change of R‐AUSRL coordination ability to the cis?/trans‐MCHAs was very large, but that of S‐AUSRL was small. Overall, the stability of the R‐series coordination complexes was higher than that of the corresponding S‐series coordination complexes, and the R‐AUSRL receptor had better coordination selectivity and higher molecular recognition to the cis?/trans‐MCHA guests than the S‐AUSRL receptor. However, the coordination ability of S‐AUSRL with the cis?/trans‐MCHAs was stronger than that of R‐AUSRL. It was expected that these results could provide insightful information and theoretical guidance for understanding the molecular recognition of R‐/S‐AUSRLs for cis?/trans‐type cyclohexylamine derivatives.     

The (+)‐cis‐ and (+)‐trans‐Olibanic Acids: Key Odorants of Frankincense

Frankincense (olibanum) is one of the oldest aromatic materials used by humans, but the key molecular constituents contributing to its characteristic odor remained unknown. Reported herein is the discovery that (1S,2S)‐(+)‐trans‐ and (1S,2R)‐(+)‐cis‐2‐octylcyclopropyl‐1‐carboxylic acids are highly potent and substantive odorants occurring in ppm amounts in all of the frankincense samples analyzed, even those showing radically different volatile compositions. These cyclopropyl‐derived acids provide the very characteristic old churchlike endnote of the frankincense odor.     

Asymmetric Synthesis of the cis‐ and trans‐3,4‐Dihydro‐2,4,8‐trihydroxynaphthalen‐1(2H)‐ones

A short and efficient protocol for the asymmetric synthesis of cis‐ and trans‐3,4‐dihydro‐2,4,8‐trihydroxynaphthalen‐1(2H)‐one ( 1 and 2 , resp.) is described, with a phthalide annulation as the key step. Introduction of a OH substituent at position 2 was performed by Sharpless dihydroxylation of a silyl enol ether or by means of an N‐sulfonyloxaziridine. The absolute configuration of each isomer was determined via Mosher‐ester derivatives. By comparison with previously recorded CD spectra of our natural sample, we established that the natural trans‐ and cis‐isomers from Ceratocystis fimbriata sp. platani were the (?)‐(2S,4S)‐isomer (?)‐ 2 and the (+)‐(2S,4R)‐isomer (+)‐ 1 , respectively.     

Asymmetric hydrogenation of ketones catalyzed by silica‐supported chitosan‐iron‐nickel complex

A new silica‐supported biopolymer‐metal complex, silica‐supported chitosan‐iron‐nickel complex was prepared by a very simple method. This complex catalyst can be used as a catalyst in the asymmetric hydrogenation of propiophenone to (R)‐(+)‐1‐phenyl‐1‐propanol and acetophenone to (R)‐(+)‐1‐phenyl ethanol in 91.7 and 77.7% optical yields, respectively, at 110°C and under 70 kg/cm² pressure. The catalyst could be reused several times without any remarkable change in the catalytic activity. Copyright © 2004 John Wiley & Sons, Ltd.     

Stereoselective Synthesis of (−)‐(1R,1′R,5′R,7′R)‐1‐Hydroxy‐exo‐brevicomin and (+)‐exo‐Brevicomin from 3,4,6‐Tri‐O‐acetyl‐D‐glucal

Stereoselective syntheses of (?)‐(1R,1′R,5′R,7′R)‐1‐hydroxy‐exo‐brevicomin ( 1 ) and (+)‐exo‐brevicomin ( 2 ) were accomplished from 3,4,6‐tri‐O‐acetyl‐D ‐glucal ( 5 ; Schemes 2 and 3). Chemoselective reduction, Grignard reaction, Barton? McCombie deoxygenation, and ketalization were used as key steps.     

Highly Diastereoselective,Biogenetically Patterned Synthesis of (+)‐(1S,6R)‐Volvatellin (=(+)‐(4R,5S)‐5‐Hydroxy‐4‐(5‐methyl‐1‐methylenehex‐4‐en‐2‐ynyl)cyclohex‐1‐ene‐1‐carbaldehyde)

The synthesis of volvatellin ( 4a ), previously isolated from a herbivorous marine mollusk, was achieved with high diastereoselectivity from putative dietary oxytoxin‐1 ( 2 ). A biogenetically patterned carbonyl‐ene route was chosen, proceeding from 2 predominantly via the trans cyclization product 3 without the use of enzymes. This challenges the involvement of enzymes in the formation of 4a in nature. The optical purity and absolute configuration (1S,4S,6R), assigned to 3 from high‐field ¹H‐NMR examination of its Mosher (MTPA) esters 6 , was retained on its chemical conversion to (+)‐(1S,6R)‐configured 4a and is consistent with the (4S) configuration previously established for caulerpenyne ( 1 ).     

A Practical and Enantiospecific Synthesis of (−)‐(R)‐ and (+)‐(S)‐Piperidin‐3‐ols

A highly enantiospecific, azide‐free synthesis of (?)‐(R)‐ and (+)‐(S)‐piperidin‐3‐ol in excellent yield was developed. The key step of the synthesis involves the enantiospecific ring openings of enantiomerically pure (R)‐ and (S)‐2‐(oxiran‐2‐ylmethyl)‐1H‐isoindole‐1,3(2H)‐diones with the diethyl malonate anion and subsequent decarboxylation.     

Estimating the lipophilicity of a number of 2‐amino‐1‐cyclohexanol derivatives exhibiting anticonvulsant activity

The lipophilicity of a number of N‐acyl derivatives of trans‐ or cis‐: racemic, (1R,2R)‐ or (1S,2S)‐aminocyclohexanol (1–13) exhibiting anticonvulsant activity was investigated. Their lipophilicity (R_{m 0}) was determined using reversed‐phase thin‐layer chromatography (RP‐TLC) with mixtures of methanol and water as mobile phases. The partition coefficients of compounds 1–13 (log P) were also calculated using two computer programs (Pallas and Chem DU) and compared with R_{m 0}. Copyright © 2009 John Wiley & Sons, Ltd.     

Optical Resolution of 5‐Oxo‐1‐Phenyl‐Pyrazolidine‐3‐Carboxylic Acid as a New Organocatalyst for Organic Reactions

Optical resolution of racemic 5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid 2 with L‐amino acid methyl ester via the diastereomers formation was investigated. Treatment of racemic 5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid 2 with L‐valine methyl ester gave diastereomers with a total yield of 86%. The diastereomeric dipeptides can be easily separated by flash column chromatography. Acidic cleavage of the derived diastereomers gave both the optically pure (+)‐(R)‐ and (‐)‐(S)‐5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid ((+)‐(R)‐ 2 and (‐)‐(S)‐ 2 ) with a total yield of 94% and 95%, respectively.     

Asymmetric hydration of alkenes catalyzed by wool‐palladium complex

A wool‐palladium complex has been found to be able to catalyze the asymmetric hydration of 1‐octene to (S)‐(+)‐2‐octanol and 1‐decene to (R)‐(+)‐2‐decanol under 1 atm N₂ and at 70°C. The optical yields were greatly affected by Pd content in wool‐palladium complex, reaction time and so on, when the proper conditions were selected, (S)‐(+)‐2‐octanol and (R)‐(+)‐2‐decanol could be obtained in 83.2 and 75.6%e.e. optical yield respectively. This chiral natural biopolymer‐palladium complex catalyst was very easy to prepare and could be reused several times without appreciable change in catalytic activity. Copyright © 2004 John Wiley & Sons, Ltd.     

The chiral bioconversion and preclinical pharmacokinetic analysis of (R)‐(+)‐rabeprazole in beagle dogs by HPLC and HPLC‐MS/MS

In order to accurately investigate the preclinical pharmacokinetics of (R)‐(+)‐rabeprazole sodium injection, a reliable high‐performance liquid chromatography (HPLC) method was developed using a Chiral‐AGP column to prove that there is no chiral bioconversion of (R)‐(+)‐rabeprazole to (S)‐(?)‐rabeprazole in beagle dogs after single intravenous administration of (R)‐(+)‐rabeprazole sodium injection. An HPLC–tandem mass spectrometry (HPLC‐MS/MS) method for analysis of (R)‐(+)‐rabeprazole was developed and validated, and used to acquire the pharmacokinetic parameters in beagle dogs. (R)‐(+)‐Rabeprazole and internal standard omeprazole were extracted from plasma samples by protein precipitation and separated on a C₁₈ column using methanol–5 mm ammonium acetate as mobile phase. Detection was performed using a turbo‐spray ionization source and mass spectrometric positive multi‐reaction monitoring mode. The linear relationship was achieved in the range from 2.5 to 5000 ng/mL. The method also afforded satisfactory results in terms of sensitivity, specificity, precision, accuracy and recovery as well as the stability of the analyte under various conditions, and was successfully applied to a preclinical pharmacokinetic study in beagle dogs after single intravenous administrations of (R)‐(+)‐rabeprazole sodium injection at 0.33, 2 and 6 mg/kg. Copyright © 2013 John Wiley & Sons, Ltd.     

AlIII‐Catalysed Formation of Poly(limonene)carbonate: DFT Analysis of the Origin of Stereoregularity

Amino‐triphenolate derived Al^III complexes combined with suitable nucleophiles have been investigated as binary catalysts for the coupling of limonene oxide and carbon dioxide to afford alternating polycarbonates. These catalysts are able to produce stereoregular, perfectly alternating trans‐polymers from cis‐limonene oxide, whereas the pure trans isomer and cis/trans mixture give rise to lower degrees of stereoregularity. The best Al^III catalyst shows the potential to mediate the conversion of both stereoisomers of limonene oxide with high conversion levels of up to 71 % under neat conditions, indicating the high degree of robustness and atom‐efficiency of this catalytic process. Computational studies have revealed unique features of the binary catalyst system, among which is the preferred nucleophilic attack on the quaternary carbon centre in the limonene oxide substrate.     

Synthesis of a Novel C2‐Symmetric Bis‐oxazoline (=Bis[4,5‐dihydrooxazole]) and Its Application as Chiral Ligand in Asymmetric Transition Metal Catalysis

The new C₂‐symmetric bis‐oxazoline (=bis[4,5‐dihydrooxazole]) 2 with a chiral trans‐(2R,3R)‐2,3‐bis(3,5‐diphenylphenyl)cyclopropylidene (=trans‐(2R,3R)‐2,3‐bis([1,1′: 3′,1″‐terphenyl]‐5′‐yl)cyclopropylidene) backbone was efficiently synthesized (Scheme). All synthetic steps were easy to perform and led to the desired product in good overall yields. Compound 2 was tested and compared as ligand in several enantioselective catalytic reactions such as palladium(0)‐catalyzed enantioselective allylic alkylations and copper(I)‐catalyzed enantioselective cyclopropanations and aziridinations.     

Chemo‐Enzymatic Synthesis and Determination of the Absolute Configuration of Both Enantiomers of Methyl trans‐5‐Oxo‐2‐pentylpyrrolidine‐3‐carboxylate Precursors of the Aza Analogues of (+)‐ and (−)‐Methylenolactocin

Enantiomerically pure methyl esters of (+)‐(2R,3S)‐ and (−)‐(2S,3R)‐5‐oxo‐2‐pentylpyrrolidine‐3‐carboxylic acid with 99% and 98% ee were obtained by enzymatic resolution of the corresponding racemic mixture using α‐chymotrypsin and pig‐liver acetone powder, respectively. Their absolute configurations were established by chemical methods, i.e., conversion of the trans‐γ‐lactam moiety to the corresponding γ‐lactone of known configuration. The favorable interactions between the trans‐γ‐lactam and α‐chymotrypsin were rationalized by molecular‐mechanics calculations, which suggest a different situation for the cis‐diastereoisomer.     

Functional carbo‐Butadienes: Nonaromatic Conjugation Effects through a 14‐Carbon, 24‐π‐Electron Backbone

A systematic study of carbo‐butadiene motifs not embedded in an aromatic carbo‐benzene ring is described. Dibutatrienylacetylene (DBA) targets R¹?C(R)?C?C?C(Ph)?C≡C?C(Ph)?C?C?C(R)?R² are devised, in which R is C≡CSiiPr₃ and R¹ and R² are R, H, or 4‐X‐C₆H₄, with the latter including three known representatives (X: H, NMe₂, or NH₂). The synthesis method is based on the SnCl₂‐mediated reduction of pentaynediols prepared by early or late divergent strategies; the latter allows access to a OMe–NO₂ push–pull diaryl‐DBA. If R¹ and R² are H, an over‐reduced dialkynylbutatriene (DAB) with two allenyl caps was isolated instead of the unsubstituted DBA. If R¹=R²=R, the tetraalkynyl‐DBA target was obtained, along with an over‐reduced DBA product with a 12‐membered 1,2‐alkylidene‐1H₂,2H₂‐carbo‐cyclobutadiene ring. X‐ray crystallography shows that all of the acyclic DBAs adopt a planar trans–transoid–trans configuration. The maximum UV/Vis absorption wavelength is found to vary consistently with the overall π‐conjugation extent and, more intriguingly, with the π‐donor character of the aryl X substituents, which varies consistently with the first (reversible) reduction potential and first (irreversible) oxidation peak, as determined by voltammetry.