Probes for Narcotic Receptor Mediated Phenomena

The synthesis of a series of epoxy 5‐phenylmorphans is being explored in order to determine the conformational requirements of the phenolic ring in a phenylmorphan molecule that may be needed both for binding to a specific opioid receptor and for exhibiting opioid agonist or antagonist activity. Of the twelve possible ortho‐ and para‐bridged isomers (a–f) (Fig. 1), we now report the synthesis of the para‐d isomer, rac‐(3R,6aS,11aR)‐2‐methyl‐1,3,4,5,6,11a‐hexahydro‐2H‐3,6a‐methanobenzofuro[2,3‐c]azocin‐8‐ol ( 3 ). Compound 3 was synthesized via construction of the 5‐phenylazabicyclo[3.3.1]non‐3‐ene skeleton (Scheme 1) and subsequent closure of the epoxy bridge (Scheme 2). As determined by an X‐ray diffraction study, the epoxy bridge, restricting the phenyl‐ring rotation, fixed the dihedral angle between the least‐squares planes through the phenyl ring and atoms N(2), C(3), C(11a), and C(6a) of the piperidine ring (Fig. 2) at 43.0°, and the torsion angle C(12)? C(6a)? C(6b)? C(10a) at ?95.0°.     

Formation of mixed-ligand complexes in the complexing polymer sorbent-Pb<Superscript>2+</Superscript>-dinitrophenol systems

The complexation of lead(II) with a group of synthesized sorbents based on aminopolystyrene and substituted phenols having structurally different substituents of various electronic natures in the para position with respect to phenolic hydroxyl was studied. As third components, α-dinitrophenol and γ-dinitrophenol were examined. The following most important parameters of sorption were determined: the optimum pH value of quantitative sorption (pH_opt), the recovery (R, %), the sorption capacity of the sorbent (SCS_Pb, mg/g), the half-sorption pH value (pH₅₀), and the temperature and time (τ) of sorption in the presence of a third component. The structure of the mixed-ligand complex was determined.     

A tetrahydropentaleno[1,6a‐a]naphthalen‐4(2H)‐one of defined relative stereochemistry for use towards Agariblazeispirol C

Towards the synthesis of the novel natural product Agariblazeispirol C, (5aR*,11bR*)‐9‐methoxy‐3,8,11b‐trimethyl‐5,6,7,11b‐tetrahydro‐1H‐pentaleno[1,6a‐a]naphthalen‐4(2H)‐one, C₂₀H₂₄O₂, has been prepared at a key stage of the preparative programme. The structure shows the desired stereochemical outcome of the central cyclization protocol, viz. a syn‐relationship between the aliphatic methyl group on the 11b‐position and the methylene group on the 5a‐position [C—C—C—C = −34.57 (18)°].     

Samaderin B and C from Samadera indica

Samaderin B, or (1R,2S,5R,5aR,7aS,11S,11aS,11bR,14S)‐1,7,7a,11,11a,11b‐hexa­hydro‐1,11‐di­hydroxy‐8,11a,14‐tri­methyl‐2H‐5a,2,5‐(methan­oxy­metheno)­naphth­[1,2‐d]­oxepine‐4,6,10(5H)‐trione, C₁₉H₂₂O₇, and samaderin C, or (1R,2S,5R,5aR,7aS,10S,11S,11aS,11bR,14S)‐7,7a,10,11,11a,11b‐hexa­hydro‐1,10,11‐tri­hydroxy‐8,11a,14‐tri­methyl‐2H‐5a,2,5‐(methan­oxy­metheno)­naphth­[1,2‐d]­oxepine‐4,6(1H,5H)‐dione, C₁₉H₂₄O₇, were isolated from the seed kernels of Samadera indica and were shown to exhibit antifeedant activity against Spodoptera litura third‐instar larvae. The replacement of the carbonyl group in samaderin B by a hydroxy group in samaderin C causes conformational changes at the substitution site, but the overall conformation is not affected; however, the compounds pack differently in the crystal lattice.     

Three new dihydro‐β‐agarofuran sesquiterpenes from the seeds of Maytenus boaria

As part of a project studying the secondary metabolites extracted from the Chilean flora, we report herein three new β‐agarofuran sesquiterpenes, namely (1S,4S,5S,6R,7R,8R,9R,10S)‐6‐acetoxy‐4,9‐dihydroxy‐2,2,5a,9‐tetramethyloctahydro‐2H‐3,9a‐methanobenzo[b]oxepine‐5,10‐diyl bis(furan‐3‐carboxylate), C₂₇H₃₂O₁₁, ( II ), (1S,4S,5S,6R,7R,9S,10S)‐6‐acetoxy‐9‐hydroxy‐2,2,5a,9‐tetramethyloctahydro‐2H‐3,9a‐methanobenzo[b]oxepine‐5,10‐diyl bis(furan‐3‐carboxylate), C₂₇H₃₂O₁₀, ( III ), and (1S,4S,5S,6R,7R,9S,10S)‐6‐acetoxy‐10‐(benzoyloxy)‐9‐hydroxy‐2,2,5a,9‐tetramethyloctahydro‐2H‐3,9a‐methanobenzo[b]oxepin‐5‐yl furan‐3‐carboxylate, C₂₉H₃₄O₉, ( IV ), obtained from the seeds of Maytenus boaria and closely associated with a recently published relative [Paz et al. (2017). Acta Cryst. C 73 , 451–457]. In the (isomorphic) structures of ( II ) and ( III ), the central decalin system is esterified with an acetate group at site 1 and furoate groups at sites 6 and 9, and differ at site 8, with an OH group in ( II ) and no substituent in ( III ). This position is also unsubstituted in ( IV ), with site 6 being occupied by a benzoate group. The chirality of the skeletons is described as 1S,4S,5S,6R,7R,8R,9R,10S in ( II ) and 1S,4S,5S,6R,7R,9S,10S in ( III ) and ( IV ), matching the chirality suggested by NMR studies. This difference in the chirality sequence among the title structures (in spite of the fact that the three skeletons are absolutely isostructural) is due to the differences in the environment of site 8, i.e. OH in ( II ) and H in ( III ) and ( IV ). This diversity in substitution, in turn, is responsible for the differences in the hydrogen‐bonding schemes, which is discussed.     

Isolation from the Mediterranean Stolonifern Coral Sarcodictyon roseum of Sarcodictyin C,D, E,and F,novel diterpenodic alcohols esterified by (E)- or (Z)-N(1)-methylurocanic acid. Failure of the carbon-skeleton type as a classification criterion

It is shown here that the stoloniferan coral Sarcodictyon roseum of east Pyrenean waters contains four novel diterpenoids, sarcodictyin C ((?) -3 ), D ((?) -4 ), E ((+)- 5 ), F ((+)- 6 ), which are related to sarcodictyin A ( = (?)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z-7,10-epoxy-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methyoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)-benzocyclodecen-11-yl (E)-N¹-methylyrocanate; ((?)? 1 ), previously isolated from the same coral. Sarcodictyin C ((?) -3 ) and D ((?) -4 ) and the 3α-hydroxy and 3α-acetoxy derivatives of (?) -1 ), sarcodictyin E ((+) -5 ) is the (Z)-urocanate isomer of (?) -3 ), and sarcodictyin F ((+) -6 ) is the 1α-hydroxy-2-ene isomer of (?) -3 . In all cases, the nine-membered ring is locked, and the molecule stabilized, by the urocanic appendage; when this is removed in MeOH/KOH, the C(11)–O^? function is free to attack at C(5), and retro-condensations then lead to the ring-contracted butenolides 11 (from (?) -3 ) or 10 (from(?) -1 ) with extrusion of the hydroxyfuran nucleus (Scheme 3). Under the same conditions, with (?) -3 , the C(3)-O^? group competitively attacks at C(5), the hydroxyfuran nucleus is expelled, and aldehyde 14 is formed. Peculiarly, in the reaction of (?) -3 with MeOD/KOD, the ring-contracted butenolide 17 contains D at the 4′-ax position. The sarcodictyins are unique in these chemical properties, not shared by the cladiellanes which have the same C-skeleton.     

Role of para-substituted phenols in curing resole-type phenolic resins

Certain para-substituted phenols, namely, those phenols without ortho substituents and containing an electron-attracting atom or group in the para position, e.g. p-nitro-, p-bromo-, and p-chlorophenol, hasten gelation of etherified phenolic resoles. A mechanism involving cleavage of dibenzyl ether linkages in these resins is proposed to explain gelation.     

A novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (−)-shikimic acid

Oseltamivir phosphate 1 was synthesized starting from a readily available acetonide, that is, ethyl (3R,4S,5R)-3,4-O-isopropylidene shikimate 2, through a new route via 11 steps and in 44% overall yield. The synthesis described in this article is characterized by two particular steps: the highly regioselective and stereoselective facile nucleophilic replacement of an OMs by an N₃ group at the C-3 position of ethyl (3R,4S,5R)-3,4-O-bismethanesulfonyl-5-O-benzoyl shikimate 5, and the mild ring-opening of an aziridine with 3-pentanol at the C-1 position of ethyl (1S,5R,6S)-7-acetyl-5-benzoyloxy-7-azabicyclo[4,1,0]hept-2-ene-3-carboxylate 8.     

Kinetik der Bromierung von Phenolen und phenolischen Mehrkernverbindungen, 5. Mitt.

The kinetics of the bromination of six differently substituted 2,6-bis(hydroxybenzyl)phenols having only one reactivepara position at the phenolic unit in the middle of the molecule were studied in acetic acid at 22°C. The reaction rate decreases if intramolecular hydrogen bonds between one or two hydroxy groups of the adjacent phenolic units and the hydroxy group of the reacting unit become possible, and it is especially low, if these hydrogen bonds are directed to the middle by bulky substituents inortho position. This must be explained by a smaller +M-effect of the hydroxy group of the reacting unit. A kinetic isotope effect is observed in deutero acetic acid, where the reaction rate is decreased by the same amount for compounds with and without intramolecular hydrogen bonds.

     

Five (1H‐pyrrol‐2‐yl)­pyridines

The title (1H‐pyrrol‐2‐yl)­pyridines, C₉H₈N₂, substituted at the ortho, meta, and para positions of the pyridine ring all have hydrogen‐bonded arrangements with geometrically similar, nearly linear, N(pyrrole)—H⋯N(pyridine) hydrogen bonds of average length. The graph sets for the ortho, meta, and three para polymorphs are R(10), C(6), C(7), C(7), and R(28), respectively.     

Cyclohexanecarboxylic-Acid Derivatives from Psiadia trinervia

From a MeOH extra of Psiadia trinervia, seven phenolic compounds were isolated by gel filtration and reversed-phase chromatography. Six of them are known compounds, namely 3,4-di-O-caffeoylquinic acid ( 2 ), 3,5-di-O-caffeoylquinic acid ( 3 ), caffeic acid, and three 3-methoxyflavonoids. Compound 1 is a 3,4-di-O-caffeoyl derviative of (1S,3R,4R,5R)-1,3,4, 5-tetrahydroxycyclohexanecarboxylic acid, a novel steroisomer of (?)-quinic acid. Following hydrolytic treatment of the MeOH extract, ethyl 3-O-caffeoylquinate ( 4 ), ethyl 3,4-di-O-caffeoylquinate ( 5 ), and ethyl 3,5-O-caffeoylquinate ( 6 ) were isolated. The latter three compounds are artifacts. The configuration of 1-3 was established by NMR and CD (exciton chirality method).     

Absolute structures and conformations of the spongian diterpenes spongia‐13(16),14‐dien‐3‐one,epispongiadiol and spongiadiol

The absolute configurations of spongia‐13(16),14‐dien‐3‐one [systematic name: (3bR,5aR,9aR,9bR)‐3b,6,6,9a‐tetramethyl‐4,5,5a,6,8,9,9a,9b,10,11‐decahydrophenanthro[1,2‐c]furan‐7(3bH)‐one], C₂₀H₂₈O₂, (I), epispongiadiol [systematic name: (3bR,5aR,6S,7R,9aR,9bR)‐7‐hydroxy‐6‐hydroxymethyl‐3b,6,9a‐trimethyl‐3b,5,5a,6,7,9,9a,9b,10,11‐decahydrophenanthro[1,2‐c]furan‐8(4H)‐one], C₂₀H₂₈O₄, (II), and spongiadiol [systematic name: (3bR,5aR,6S,7S,9aR,9bR)‐7‐hydroxy‐6‐hydroxymethyl‐3b,6,9a‐trimethyl‐3b,5,5a,6,7,9,9a,9b,10,11‐decahydrophenanthro[1,2‐c]furan‐8(4H)‐one], C₂₀H₂₈O₄, (III), were assigned by analysis of anomalous dispersion data collected at 130 K with Cu Kα radiation. Compounds (II) and (III) are epimers. The equatorial 3‐hydroxyl group on the cyclohexanone ring (A) of (II) is syn with respect to the 4‐hydroxymethyl group, leading to a chair conformation. In contrast, isomer (III), where the 3‐hydroxyl group is anti to the 4‐hydroxymethyl group, is conformationally disordered between a major chair conformer where the OH group is axial and a minor boat conformer where it is equatorial. In compound (I), a carbonyl group is present at position 3 and ring A adopts a distorted‐boat conformation.     

(1R,8R,11R)‐3,3,11‐Tri­methyl‐6,6‐ethyl­ene­dioxy­bi­cyclo­[6.3.0]­undecan‐2‐one and (1R,2R,8R,11R)‐3,3,11‐tri­methyl‐6,6‐ethylenedioxybicyclo[6.3.0]undecan‐2‐ol

The reduction of (1R,8R,11R)‐3,3,11‐tri­methyl‐6,6‐ethyl­ene­dioxy­bi­cyclo­[6.3.0]­undecan‐2‐one, C₁₆H₂₆O₃, (I), gave exclusively an alcohol, C₁₆H₂₈O₃, (II). The stereochemistry of the hydroxyl group in (II) was shown as R. The conformation around the eight‐membered carbocycle in (I) differs markedly from that in (II).     

Phenolic Metabolites from the Stems and Leaves of Sophora flavescens

Two new compounds, (?)‐(6aR,11aR)‐4‐methoxy‐8,9‐(methylenedioxy)pterocarpan 3‐O‐β‐D ‐glucopyranoside ( 1 ) and 5‐hydroxy‐7‐methoxyisoflavone 4′‐O‐β‐D ‐xylopyranosyl‐(1→6)‐β‐D ‐glucopyranoside ( 2 ), were isolated, together with 30 known compounds from the stems and leaves of Sophora flavescens Aition . Their structures were elucidated by extensive spectroscopic analysis, including HR‐ESI‐MS data. A preliminary comparison of phenolic metabolite profiles, based on the qualitative HPLC analysis, indicated that the composition of the roots and the aerial parts were significantly different.     

2,4,6‐Trimethyl‐N‐nitro­aniline

In 2,4,6‐trimethyl‐N‐nitro­aniline (alternatively called mesitylnitramine), C₉H₁₂N₂O₂, the primary nitramino group is planar with a short N—N bond and is nearly perpendicular to the aromatic ring. The methyl group located in the para position is disordered, each H atom having half‐occupancy. The mol­ecules are linked together along the [100] axis by inter­molecular N—H⋯O hydrogen bonds.     

A new biologically active molecular scaffold: crystal structure of 7‐(3‐hydroxyphenyl)‐4‐methyl‐2H‐[1,2,4]triazolo[3,2‐c][1,2,4]triazole and selective antiproliferative activity of three isomeric triazolo–triazoles

A study of three isomeric compounds containing a phenolic moiety attached to the nitrogen‐rich triazolo–triazole bicycle is presented. In the three isomers, the phenolic OH group is in the ortho, meta and para positions. The crystal structure analysis of the meta isomer (C₁₀H₉N₅O) shows that the 2H‐tautomer is present in the crystal and that the molecule adopts a substantially planar geometry. However, the conformation found in the crystal is different compared to the monoprotonated cation of the same compound previously investigated in several salts. The packing of the meta isomer is driven by the formation of strong hydrogen bonds and shows the formation of infinite planar ribbons, parallel to a, formed around 2₁ crystallographic axes. The three isomers were tested against some cancer cell lines and also against normal cell lines. The ortho isomer shows a weak antiproliferative activity, the meta isomer shows significant antiproliferative activity against some cancer lines and no activity against healthy cell lines, and the para isomer is active against all the tested cell lines.     

17O NMR studies of ortho‐substituent effects in substituted phenyl tosylates

¹⁷O NMR spectra for 35 ortho‐, para‐, and meta‐substituted phenyl tosylates (phenyl 4‐methylbenzenesulfonates), 4‐CH₃‐C₆H₄SO₂OC₆H₄‐X, at natural abundance in acetonitrile at 50 °C were recorded. The ¹⁷O NMR chemical shifts, δ(¹⁷O), of the sulfonyl (SO₂) and the single‐bonded phenoxy (OPh) oxygens for para and meta derivatives correlated well with dual substituent parameter treatment using the Taft inductive, σ_I, and resonance, σº_R, constants. The influence of ortho substituents on the sulfonyl oxygen and the single‐bonded phenoxy oxygen chemical shifts, δ(¹⁷O), was found to be nicely described by the Charton equation: δ(¹⁷O)_ortho = δ(¹⁷O)_H + ρ_Iσ_I + ρ_Rσ°_R + δE_s^B when the data treatment was performed separately for electron‐donating +R substituents and electron‐attracting ?R substituents. Electron‐attracting meta and para substituents in the phenyl moiety caused deshielding while the electron‐donating meta, para and ortho +R substituents produce shielding effects on the sulfonyl (SO₂) and single‐bonded phenoxy (OPh) oxygens. The influence of ortho inductive and resonance effects in the case of +R substituents was found to be approximately twice higher than the corresponding influence from the para position. Due to the steric effect of ortho substituents a decrease in shielding of the oxygens at the sulfonyl group (δE_s^B > 0, E_s^B < 0) was detected. Copyright © 2012 John Wiley & Sons, Ltd.     

Total Synthesis of (+)‐Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

The enantioselective total synthesis of (+)‐gracilamine ( 1 ) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza‐Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza‐Friedel–Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)‐gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.     

Humulene and its derivatives from <Emphasis Type="Italic">Betula pendula</Emphasis> buds

Humulene and its derivatives (6R)-hydroxy-α-humulene [(6R)-hydroxy-(1E,4E,8E)-4,8,11,11tetramethylcycloundeca-1,4,8-triene], (6R)-acetoxy-α-humulene [(6R)-acetoxy-(1E,4E,8E)-4,8,11,11tetramethylcycloundeca-1,4,8-triene], a coumaric acid ester, 14-hydroxy-α-humulene [14-coumaroxy(1E,4E,8E)-4,8,11,11-tetramethylcycloundeca-1,4,8-triene], (1E,6R,8E)-4,5-epoxy-6-hydroxy-4,8,11,11tetramethylcycloundeca-1,8-diene, and (6R,9S)-4,11,11-trimethyl-8-methylene-1,4-cycloundecadien-6,9-diol were observed in the hydrocarbon extract of Betula pendula (Betulaceae) buds. The GC retention indices were determined for all identified compounds.     

3,6-Thioanhydro sugar derivatives. An enantiospecific synthesis of (2R,3R,4S)-3-benzyloxy-4-hydroxy-2-[(R)-1-benzyloxy-4-hydroxybutyl]thiolane as the key intermediate for thioswainsonine

Methyl 2-O-benzyl-3,6-thioanhydro-α-D-mannopyranoside ( 9 ) was obtained in eight steps from the commercially available methyl α-D-glucopyranoside. Compound 9 was transformed into (2R,3R,4S)-3-benzyloxy-4-hydroxy-2-[(R)-1-benzyloxy-4-hydroxybutyl]thiolane ( 14 ) by acid hydrolysis of its 2,4-di-O-benzyl derivative 10 followed by reaction of the not isolated 2,4-di-O-benzyl-3,6-thioanhydro-D-mannose ( 11 ) with ethoxycarbonylmethylenetriphenylphosphorane to give an = 1:1 E/Z mixture of the corresponding α,β-unsaturated ester ( 12 ). Finally, catalytic hydrogenation of 12 to ethyl (R)-4-benzyloxy-4-[(2′R)3′R,4′S)-3′-benzyloxy-4′-hydroxythiolan-2′-yl]butanoate ( 13 ) and subsequent reduction with lithium aluminum hydride gave the title compound 14 .