Reactions of Allyl Alcohols of the Pinane Series and of Their Epoxides in the Presence of Montmorillonite Clay

The reactivity of allyl alcohols of the pinane series and of their epoxides in the presence of montmorillonite clay in intra‐ and intermolecular reactions was studied. Mutual transformations of (+)‐trans‐pinocarveol ((+)‐ 2 ) and (?)‐myrtenol ((?)‐ 3a ) were major reactions of these compounds on askanite–bentonite clay (Schemes 1 and 2). However, the two reactions gave different isomerization products, indicating that the reactivity of the starting alcohol (+)‐ 2 or (?)‐ 3a was different from that of the same compound (+)‐ 2 or (?)‐ 3 formed in the course of the reactions. (?)‐cis‐ and (+)‐trans‐Verbenol ((?)‐ 16 and (+)‐ 12 , resp.), as well as (?)‐cis‐verbenol epoxide ((?)‐ 20 ) reacted with both aliphatic and aromatic aldehydes on askanite–bentonite clay giving various heterocyclic compounds (Schemes 4, 5 and 7); the reaction path depended on the structure of both the terpenoid and the aldehyde.     

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 .     

Synthesis,Olfactory Evaluation,and Determination of the Absolute Configuration of the 3,4‐Didehydroionone Stereoisomers

The synthesis of 3,4‐didehydroionone isomers 4 , (+)‐ 6 , and (?)‐ 6 and of 3,4‐didehydro‐7,8‐dihydroionone isomers 5 , (+)‐ 7 , and (?)‐ 7 was accomplished starting from commercially available racemic α‐ionone ( 1 ). Their preparation of the racemic forms 4 – 7 was first achieved by mean of a number of chemo‐ and regioselective reactions (Schemes 1 and 2). The enantio‐ and diastereoselective lipase‐mediated kinetic acetylation of 4‐hydroxy‐γ‐ionone ( 10a / 10b ) provided 4‐hydroxy‐γ‐ionone (+)‐ 10a /(±)‐ 10b and (+)‐4‐(acetyloxy)‐γ‐ionone ((+) 12b ) (Scheme 3). The latter compounds were used as starting materials to prepare the 3,4‐didehydro‐γ‐ionones (+)‐ and (?)‐ 6 and the 3,4‐didehydro‐7,8‐dihydro‐γ‐ionones (+)‐ and (?)‐ 7 in enantiomer‐enriched form. The absolute configuration of (+)‐ 12b was determine by chemical correlation with (+)‐(6S)‐γ‐ionone ((+)‐ 3 ) and with (?)‐(6S)‐α‐ionone ((?)‐ 1 ) therefore allowing to assign the (S)‐configuration to (+)‐ 6 and (+)‐ 7 . Olfactory evaluation of the above described 3,4‐didehydroionone isomers shows a significant difference between the enantiomers and regioisomers both in fragrance feature and in detection threshold (Table).     

Total Syntheses and Biological Evaluation of Both Enantiomers of Several Hydroxylated Dimeric Nuphar Alkaloids

Herein, we describe the first total syntheses of five members of the dimeric nuphar alkaloids: (+)‐6,6′‐dihydroxythiobinupharidine (+)‐ 1 a , (+)‐6‐hydroxythiobinupharidine (+)‐ 1 b , (?)‐6,6′‐dihydroxythionuphlutine (?)‐ 2 a , (?)‐6,6′‐dihydroxyneothiobinupharidine (?)‐ 3 a , and (+)‐6,6′‐dihydroxyneothionuphlutine (+)‐ 4 a . The latter two have not been found in nature. We have also made each of their enantiomers (?)‐ 1 a – b , (+)‐ 2 a , (+)‐ 3 a , and (?)‐ 4 a . The key step in these syntheses was the dimerization of an α‐aminonitrile (a hydrolytically stable surrogate for its corresponding hemiaminal) with chiral Lewis acid complexes. We have also reassigned the literature structures of (+)‐ 1 a – 1 b —for those instances in which the NMR spectra were obtained in CD₃OD—to their corresponding CD₃O‐adducts. Our efforts provide for the first time apoptosis data for (?)‐ 3 a , (+)‐ 4 a , and all five non‐natural enantiomers prepared. The data indicate high apoptotic activity regardless of the enantiomer or relative stereochemical configuration at C7 and C7′.     

A Concise and Highly Enantioselective Total Synthesis of (+)‐anti‐ and (−)‐syn‐Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines

A concise asymmetric (>99:1 e.r.) total synthesis of (+)‐anti‐ and (?)‐syn‐mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless‐derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)‐anti‐ and (?)‐syn‐mefloquine, respectively. The synthetic (+)‐anti‐ and (?)‐syn‐mefloquine samples were derivatized with (S)‐(+)‐mandelic acid tert‐butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X‐ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)‐anti‐ as well as (?)‐syn‐mefloquine.     

The Absolute Configuration of (+)‐Ethyl cis‐1‐Benzyl‐3‐hydroxypiperidine‐4‐carboxylate and (+)‐4‐Ethyl 1‐Methyl cis‐3‐Hydroxypiperidine‐1,4‐dicarboxylate; a Revision

Discrepancies between chiroptical data from the literature and our determination of the structure of the title compounds (+)‐ 5 and (+)‐ 9a were resolved by an unambiguous assignment of their absolute configuration. Accordingly, the dextrorotatory cis‐3‐hydroxy esters have (3R,4R)‐ and the laevorotatory enantiomers (3S,4S)‐configuration. The final evidences were demonstrated on both enantiomers (+)‐ and (?)‐ 5 by biological reduction of 4 by bakers' yeast and stereoselective [Ru^II(binap)]‐catalyzed hydrogenations of 4 (Scheme 2), by the application of the NMR Mosher method on (+)‐ and (?)‐ 5 (Scheme 3), as well as by the transformation of (+)‐ 5 into a common derivative and chiroptical correlation (Scheme 4).     

Asymmetric Synthesis of Both Enantiomers of Disparlure

Starting from propargyl alcohol ( 12 ), and on the basis of Zhou's modified Sharpless asymmetric epoxidation, the sex pheromone of the Gypsy moth, disparlure (+)‐ 8 and its enantiomer (?)‐ 8 have been synthesized, each in six steps, with overall yields of 29% for (+)‐ 8 and 27% for (?)‐ 8 (ee>98%). The use of the sequential coupling tactic renders the method flexible, which is applicable to the synthesis of other cis‐epoxy pheromones.     

Enantioselective Access to (−)‐Ambrox® Starting from β‐Farnesene

Starting from inexpensive (E)‐β‐farnesene ( 1 ), an eight‐step enantioselective synthesis of the olfactively precious Ambrox^® ((?)‐ 2a ) has been performed. The crucial step is the catalytic asymmetric isomerization of (2E,6E)‐N,N‐diethylfarnesylamine ( 3 ) to the corresponding enamine (?)‐(R,E)‐ 4a , applying Takasago's well‐known industrial methodology. The resulting dihydrofarnesal ((+)‐(R)‐ 5 ) (90% yield, 96% ee), obtained after in situ hydrolysis (AcOH, H₂O), was then cyclized under catalytic SnCl₄ conditions, via its corresponding unreported enol acetate (?)‐(R)‐ 4b , to afford trans‐decalenic aldehyde (+)‐ 6a . Subsequent transformations furnished bicyclic ketone (?)‐ 8a and unsaturated nitrile (+)‐ 11 , both reported as intermediates to access to (?)‐ 2a .     

A Facile Approach to Synthesis of the Di-O-methyl Ethers of （-）-Agatharesinol, （-）-Sugiresinol, （＋）-Nyasol and （＋）-Tetrahydronyasol

The facile enantioselective synthesis of the di-O-methyl ethers of （-）-agatharesinol （1b）, （-）-sugiresionl （2b）, （＋）-nyasol （3b） and （＋）-tetrahydronyasol （4） were achieved in high yield. The absolute configuration of （＋）-3a was confirmed via first total synthesis of （＋）-3b and （＋）-4.     

Pharmacokinetic study of ofloxacin enantiomers in Pagrosomus major by chiral HPLC

(S)‐(?)‐Ofloxacin and (R)‐(+)‐ofloxacin concentrations in the plasma of Pagrosomus major after drug treatment were detected by chiral high‐performance liquid chromatography, and various pharmacokinetic parameters were calculated from these data. The elimination half‐life of (S)‐(?)‐ofloxacin was significantly shorter than that of the (R)‐(+) enantiomer. (S)‐(?)‐Ofloxacin also had a significantly lower maximum plasma concentration, area under the concentration–time curve from zero to infinity, and mean residence time than (R)‐(+)‐ofloxacin. However, the apparent volume of distribution and total body clearance of (S)‐(?)‐ofloxacin were greater than those of (R)‐(+)‐ofloxacin. The ratio of the (S)‐(?)‐ to (R)‐(+)‐ofloxacin plasma concentration was always <1.0. Together, these data suggest that (S)‐(?)‐ofloxacin was preferentially excreted and (R)‐(+)‐ofloxacin was preferentially absorbed. Although the difference in pharmacokinetic parameters was small, the metabolic behavior of the ofloxacin enantiomers in P. major was enantioselective. Copyright © 2015 John Wiley & Sons, Ltd.     

(+)‐(R,Z)‐5‐Muscenone and (−)‐(R)‐Muscone by Enantioselective Aldol Reaction and Grob Fragmentation

(+)‐(R,Z)‐5‐Muscenone ((R)‐ 1 ) was synthesized by an enantioselective aldol reaction, catalyzed by new ephedrine‐type Ti reagents (up to 70 % enantiomeric excess). Substrate‐directed diastereoselective reduction of the aldol product and Grob fragmentation of the tosylate of the resultant 1,3‐diol afforded (+)‐ 1 . This approach also gave access to (?)‐(R,E)‐5‐muscenone and (?)‐(R)‐muscone.     

1‐Phenyl‐1,2‐cyclohexadiene: Astoundingly High Enantioselectivities on Generation in a Doering–Moore–Skattebøl Reaction and Interception by Activated Olefins

The resolution of (1α,5α,6α)‐6‐bromo‐6‐fluoro‐1‐phenylbicyclo[3.1.0]hexane (rac‐ 5) provided the enantiomerically pure precursors (?)‐ 5 and (+)‐ 5 of 1‐phenyl‐1,2‐cyclohexadiene. On treatment of (?)‐ 5 with methyllithium in the presence of 2,5‐dimethylfuran, the pure (?)‐enantiomer of the [4+2] cycloadduct of 2,5‐dimethylfuran onto 1‐phenyl‐1,2‐cyclohexadiene was obtained exclusively. From this result, it is concluded that pure (M)‐1‐phenyl‐1,2‐cyclohexadiene ((M)‐ 7 ) emerged from (?)‐ 5 and was enantiospecifically intercepted to give the product. In the case of indene as trap for (M)‐ 7 , the (?)‐ and the (+)‐enantiomer of the [2+2] cycloadduct were formed in the ratio of 95:5. Highly surprising, remarkable enantioselectivities were also observed, when (M)‐ 7 was trapped with styrene to furnish two diastereomeric [2+2] cycloadducts. Hence, the achiral conformation of the diradical conceivable as intermediate cannot play a decisive part. The enantioselective generation of (M)‐ and (P)‐ 7 by the β‐elimination route was tested as well. Accordingly, 1‐bromo‐2‐phenylcyclohexene was exposed to the potassium salt of (?)‐menthol in the presence of 2,5‐dimethylfuran, and the enantiomeric [4+2] cycloadducts of the latter onto (M)‐ and (P)‐ 7 were produced in the ratio of 55:45.     

Enzymatic Resolution of O‐(Methoxymethyl)‐Protected Tropane‐diols

A convenient synthetic route to enantiomerically pure tropane‐diol building blocks is described. The reaction sequence started from tropenone derivatives 1 , which were dihydroxylated to give 6,7‐dihydroxytropanone derivatives 2 . After introduction of the methoxymethyl (MOM) protecting group in diol 2a , a lipase‐mediated resolution of the resulting racemic mono‐MOM ether (±)‐ 5d with vinyl acetate and vinyl trifluoroacetate gave the acetates (?)‐ 6d and (?)‐ 6f , respectively, with 96–99% ee, and MOM ether (+)‐ 5d with up to 89% ee. Deacetylation of (?)‐ 6d afforded quantitatively MOM ether (?)‐ 5d with 99% ee, the absolute configuration of which was assigned via the modified Mosher method to be (R) at C(6). Enzymatic treatment of unprotected diol 2a with vinyl trifluoroacetate or alkoxycarbonylation resulted in the formation of C_s‐symmetrical products 9 and 12 rather than the desired desymmetrized derivatives.     

Photooxygenation of a Microbial Arene Oxidation Product and Regioselective Kornblum–DeLaMare Rearrangement: Total Synthesis of Zeylenols and Zeylenones

We report the enantioselective total syntheses of zeylenol (+)‐ 1 , as well as its congeners (?)‐ 7 and 16 , and of 3‐O‐debenzoylzeylenone 28 . To this end, a new variant of the Kornblum–DeLaMare rearrangement, which utilises neighbouring‐group participation to impart regioselectivity, has been developed. The approach employs photooxygenation of building blocks derived from a microbial arene oxidation product.     

Synthesis of [4.3.3]Propellanes by Carbenium‐Ion Rearrangement and Their Olfactory Characterization

Treatment of (+)‐sclareolide ( 1 ) with polyphosphoric acid or Eaton's reagent furnished, besides the anticipated cyclopentenone (?)‐ 12 and its isomer (?)‐ 15 , two diastereoisomeric [4.3.3]propellanes (?)‐ 13 and (?)‐ 14 , which possess interesting woody‐ambery odors. The hydrogenated derivative (?)‐ 17 possessed an even more‐powerful odor reminiscent of natural ambergris tincture. Mechanistic insight into this rearrangement was provided by a by‐product 24 of the reaction of sclareolide ( 1 ) with Eaton's reagent. The carbenium ion rearrangement was then employed in the synthesis of four related [4.3.3]propellanes 40 – 43 , illustrating the utility and scope of this reaction. The olfactory properties of the synthesized [4.3.3]propellanes as well as of the original target structures 10, 33 , and 34 , prepared from (?)‐ 12 and (?)‐ 15 , are discussed. Especially the pronounced ambra odor of (?)‐ 17 vividly contradicts the ‘triaxial rule of amber sensation' and provides new insight into the structural requirements for ambra odorants.     

Synthesis and Evaluation as Glycosidase Inhibitors of Isoquinuclidines Mimicking a Distorted β‐Mannopyranoside

Racemic and enantiomerically pure manno‐configured isoquinuclidines were synthesized and tested as glycosidase inhibitors. The racemic key isoquinuclidine intermediate was prepared in high yield by a cycloaddition (tandem Michael addition/aldolisation) of the 3‐hydroxy‐1‐tosyl‐pyridone 10 to methyl acrylate, and transformed to the racemic N‐benzyl manno‐isoquinuclidine 2 and the N‐unsubstituted manno‐isoquinuclidine 3 (twelve steps; ca. 11% from 10 ). Catalysis by quinine of the analogous cycloaddition of 10 to (?)‐8‐phenylmenthyl acrylate provided a single diastereoisomer in high yield, which was transformed to the desired enantiomerically pure D ‐manno‐isoquinuclidines (+)‐ 2 and (+)‐ 3 (twelve steps; 23% from 10 ). The enantiomers (?)‐ 2 and (?)‐ 3 were prepared by using a quinidine‐promoted cycloaddition of 10 to the enantiomeric (+)‐8‐phenylmenthyl acrylate. The N‐benzyl D ‐manno‐isoquinuclidine (+)‐ 2 is a selective and slow inhibitor of snail β‐mannosidase. Its inhibition strength and type depends on the pH (at pH 4.5: K_i=1.0 μM , mixed type, α=1.9; at pH 5.5: K_i=0.63 μM , mixed type, α=17). The N‐unsubstituted D ‐manno‐isoquinuclidine (+)‐ 3 is a poor inhibitor. Its inhibition strength and type also depend on the pH (at pH 4.5: K_i=1.2?10³ μM , mixed type, α=1.1; at pH 5.5: K_i=0.25?10³ μM , mixed type, α=11). The enantiomeric N‐benzyl L ‐manno‐isoquinuclidine (?)‐ 2 is a good inhibitor of snail β‐mannosidase, albeit noncompetitive (at pH 4.5: K_i=69 μM ). The N‐unsubstituted isoquinuclidine (?)‐ 2 is a poor inhibitor (at pH 4.5: IC₅₀=7.3?10³ μM ). A comparison of the inhibition by the pure manno‐isoquinuclidines (+)‐ 2 and (+)‐ 3 , (+)‐ 2 /(?)‐ 2 1 : 1, and (+)‐ 3 /(?)‐ 3 1 : 1 with the published data for racemic 2 and 3 led to a rectification of the published data. The inhibition of snail β‐mannosidase by the isoquinuclidines 2 and 3 suggests that the hydrolysis of β‐D ‐mannopyranosides by snail β‐mannosidase proceeds via a distorted conformer, in agreement with the principle of stereoelectronic control.     

Non‐iterative Asymmetric Synthesis of C15 Polyketide Spiroketals

The 2,2′‐methylenebis[furan] ( 1 ) was converted to 1‐{(4R,6S))‐6‐[(2R)‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2R,4R)‐tetrahydro‐4,6‐dihydroxy‐2H‐pyran‐2‐yl)propan‐2‐one ((+)‐ 18 ) and its (4S)‐epimer (?)‐ 19 with high stereo‐ and enantioselectivity (Schemes 1–3). Under acidic methanolysis, (+)‐ 18 yielded a single spiroketal, (3R)‐4‐{(1R,3S,4′R,5R,6′S,7R)‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐6′‐yl}butane‐1,3‐diol ((?)‐ 20 ), in which both O‐atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (?)‐ 20 (methyl pyranoside formation). Compound (?)‐ 19 was converted similarly into the (4′S)‐epimeric tricyclic spiroketal (?)‐ 21 that also adopts a similar (3S)‐configuration and conformation. Spiroketals (?)‐ 20 , (?)‐ 21 and analog (?)‐ 23 , i.e., (1R,3S,4′R,5R,6′R)‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2S)‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐4′‐ol, derived from (?)‐ 20 , were assayed for their cytotoxicity toward murine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic (±)‐ 21 showed evidence of cancer‐cell‐growth inhibition (P388, ED₅₀: 6.9 μg/ml).     

Bisubstrate Inhibitors for the Enzyme Catechol O‐Methyltransferase (COMT): Dramatic Effects of Ribose Modifications on Binding Affinity and Binding Mode

Inhibition of the enzyme catechol O‐methyltransferase (COMT) is of significant interest in the therapy of Parkinson's disease. Described herein are structural analogs of the potent bisubstrate inhibitor (?)‐ 1 (IC₅₀=9 nM ; Table 1) for COMT, with target modifications of the central ribose moiety. Their synthesis involves, as key intermediates, adenosine derivatives, which are transformed to the potential bisubstrate inhibitors by a similar sequence of six steps (Schemes 1–4). The compounds were submitted to an enzymatic assay for determination of their in vitro inhibitory activity against COMT, and the inhibition mechanism with respect to the binding side of the cofactor S‐adenosylmethionine (SAM) was analyzed by kinetics measurements (Fig. 3). Both binding affinity and binding mode were exceedingly sensitive towards modifications of the ribose moiety (Table 1). Removal of the 2′‐OH group upon changing from (?)‐ 1 to (?)‐ 2 (IC₅₀=28 μM ) led to a reduction in binding affinity by more than three orders of magnitude. At the same time, competitive inhibition kinetics with respect to the SAM binding site was maintained, thereby supporting a bisubstrate binding mode. Unlike (?)‐ 2 , the dideoxyribose inhibitor (?)‐ 3 (IC₅₀=3 μM ) showed a mixed and the cyclopentane derivative (+)‐ 4 (IC₅₀=1 μM ) an uncompetitive inhibition mechanism with respect to the SAM binding site. In the complex of the latter, the adenine‐substituted cyclopentane ring orients most probably towards the surface of the enzyme into the surrounding solution. The enantiomeric compounds (?)‐ 5 (IC₅₀=43 μM ) and (+)‐ 5 (IC₅₀=141 μM ), wherein the ribose had been replaced by a pyrrolidine ring, showed only low binding affinity.     

Simultaneous stereoselective analysis of naftopidil and O‐desmethyl naftopidil enantiomers in rat feces using an online column‐switching high‐performance liquid chromatography method

A novel online column‐switching chiral high‐performance liquid chromatography method was developed and validated for the simultaneous determination of naftopidil (NAF) and its O‐desmethyl metabolites (DMN) enantiomers in rat feces. Direct and multiple injections of supernatant from rat feces homogenate were allowed through the column‐switching system. Analyte extraction was performed on the Capcell Pak mixed‐functional column by acetonitrile–phosphate buffer (pH 7.4; 10 mm ; 8:92, v/v) flowing at 1 mL/min. Separation of NAF and DMN enantiomers was achieved on the Chiralpak IA column by methanol–acetonitrile–acetate buffer (pH 5.3; 5 mm ; 45:33:22, v/v/v) flowing at 0.5 mL/min. The analytes were measured with a fluorescence detector at 290 nm (λ_ex) and 340 nm (λ_em). The validated method showed a good linearity [22.5–15,000 ng/mL for (+)‐/(?)‐NAF; 35–25,000 ng/mL for (+)‐/(?)‐DMN] and the lowest limits of quantification for NAF and DMN enantiomers were 22.5 and 35 ng/mL, respectively. Both intra‐ and inter‐day variations were <10%. The assay was successfully applied to the fecal excretion of NAF and DMN enantiomers in rat after single oral administration of (±)‐NAF. Nonstereoselective excretion of (+)‐ and (?)‐NAF was found in feces, while stereoselective excretion of (+)‐ and (?)‐DMN was observed with higher excretion levels of (+)‐DMN, indicating that there may exist stereoselective metabolism for NAF enantiomers. Copyright © 2014 John Wiley & Sons, Ltd.     

Enantioselective Total Synthesis of (+)‐Jungermatrobrunin A

A concise and enantioselective total synthesis of (+)‐jungermatrobrunin A ( 1 ), which features a unique bicyclo[3.2.1]octene ring skeleton with an unprecedented peroxide bridge, was accomplished in 13 steps by making use of a late‐stage visible‐light‐mediated Schenck ene reaction of (?)‐1α,6α‐diacetoxyjungermannenone C ( 2 ). Along the way, a UV‐light‐induced bicyclo[3.2.1]octene ring rearrangement afforded (+)‐12‐hydroxy‐1α,6α‐diacetoxy‐ent‐kaura‐9(11),16‐dien‐15‐one ( 4 ). These divergent photo‐induced skeletal rearrangements support a possible biogenetic relationship between (+)‐ 1 , (?)‐ 2 , and (+)‐ 4 .