Microbial Transformation of (−)-Δ1-3,4-trans-Tetrahydrocannabinol by Cunninghamella blakesleeana LENDER

Incubation of (?)-Δ¹-3, 4-trans-tetrahydrocannabinol (= Δ¹-THC; 3 ) with stationary cultures of Cunninghamella blakesleeana LENDER (Zygomycetales) (ATCC 8688a) yielded a number of metabolic conversion products. Isolation and structure elucidation of 6α-hydroxy-Δ¹-THC ( 4 ), the potential psychoactive 3″-hydroxy-Δ¹-THC ( 2 ) and 4″-hydroxy-Δ¹-THC ( 1 ), and the hitherto unknown metabolites 4″-hydroxy-6-oxo-Δ¹-THC ( 5 ), 4″, 6α-dihydroxy-Δ¹-THC ( 7 ) and 4″, 7 -dihydroxy-Δ¹-THC ( 6 ) is described.     

Synthese von Haschisch-Inhaltsstoffen. 6. Mitteilung

The synthesis of a new (?)-Δ⁸-6a,10a-trans-tetrahydrocannabinol analogue, containing a N-methyl-3-propyl-pyrrolidin-3-yl side-chain, is reported.     

Synthese von Haschisch-Inhaltsstoffen. 5. Mitteilung

A (?)-Δ⁸-6a,10a-trans-tetrahydrocannabinol analogue, with a methyl-(3-dimethyl-amino-propyl)-amino side-chain instead of the n-pentyl radical in the naturally occurring product, has been synthesized by condensing 5-methylamino-resorcinol tosylate with (+)-trans-p-2,8-menthadien-1-ol.     

Synthese von Haschisch-Inhaltsstoffen. 4. Mitteilung

(?)-Cannabidiol has been synthesized from (+)-cis- and (+)-trans-p-menthadien-(2, 8)-ol-(1) and olivetol, using N, N-dimethylformamide dineopentyl acetal or weak acids, such as oxalic, picric, or maleic acid, as catalysts. Since the chirality of (+)-trans-p-menthadien-(2, 8)-ol-(1) is known, the above synthesis constitutes an unambiguous prove for the absolute configuration of (?)-cannabidiol and the two isomeric (?)-6a, 10a-trans-tetrahydrocannabinols. If stronger acids, such as p-toluenesulfonic, trifluoroacetic, or hydrochloric acid, are used as mediators for the reaction, (?)-Δ⁸-6a, 10a-trans-tetrahydrocannabinol is obtained as the main product. Transformation of the thermodynamically more stable Δ⁸-tetrahydrocannabinol into the less stable Δ⁹-isomer was achieved in a practically quantitative yield by addition of hydrochloric acid and elimination of the elements of hydrochloric acid by means of potassium t-amylate. If resorcinols I were used instead of olivetol in the condensation reaction with strong acids, the corresponding homologues of Δ⁸-tetrahydrocannabinol were obtained in varying yields.     

Microbial transformation of cannabinoids. Part 3: Major metabolites of (3R, 4R)-Δ1-tetrahydrocannabinol

The metabolic transformations of the psychotropic cannabinoid (3R, 4R)-Δ¹-tetrahydrocannabinol (5) (=Δ¹-THC) by cultures of Fusarium Nivale, Gibberella fujikuroi (both Ascomycetes) and Thamnidium elegans (Phycomycetes) were investigated. A number of metaboilites, 1–4 and 6–9 were isolated from the incubations, partly purified and their structures elucidated by combined gas chromatography/mass spectrometry. Four of these metabolites, 1″-hydroxy-Δ¹-THC (4) 2″-hydroxy-β¹-THC (1) 6Δ-hydroxy-ζ¹-THC (8) and 2″,6Δ-dihydroxy-Δ¹-THC (9) so far have not been reported as microbial transformation products of 5 .     

Conversion from (-)-delta-6,1-3,4-trans-tetrahydrocannabinol in (-)-delta-1,2-3,4-trans-tetrahydrocannabinol

Successive treatment of (?)-Δ^6,1-3,4-trans-tetrahydrocannabinol with hydrochloric acid/zinc chloride and potassium-t-amylate gives (?)-Δ^1,2-3,4-trans-tetrahydrocannabinol in quantitative yield.     

Furopyridines. VIII. Molecular structure and two-dimensional NMR spectral assignment of 2,14-dimethyl-8aβ-hydroxy-7,10-dioxo-5β,6β-(propano)-6α,8α-(ethanoimino)-trans-perhydroisoquinoline

This paper reports the two-dimensional nmr spectral assignment and the X-ray structural determination of 2,14-dimethyl-8β-hydroxy-7,10-dioxo-5β,6β-(propano)-6α,8α-(ethanoimino)-trans-perhydroisoquinoline V which was obtained from 7,10-dimethyl-2β-hydroxy-14-oxo-2,3-(methanoiminoethano)-3β,4β-(propano)-3,4,5,6,7,8-hexahydro-2H-pyrano[2,3-c]pyridine IV by isomerization with hydrochloric acid. Both the compounds IV and V afforded the same dimethiodide IV -2MeI, while the configurational isomer 2,14-dimethyl-8aβ-hydroxy-7,10-dioxo-5α,6β-(propano)-6α,8α-(ethanoimino)-trans-perhydroisoquinoline III gave monomethiodide III -Mel. The structures of these methiodides were also confirmed by X-ray analysis.     

The synthesis and liquid crystalline behaviour of 2-(4-n-alkoxyphenyl)-5-methylpyridines

We have synthesized a new series of polyphenylene compounds with a pyridine ring, 2-(4-n-alkoxyphenyl)-5-methylpyridines (CH₃C₅H₃NC₆H₄OC _i H_2i1) (1a-i ; the carbon number, i, of the alkoxy group is 1-9), and studied their phase transitions and mesogenicity using DSC and polarizing microscopy. In the homologous series of 1a-i , no mesomorphic phase appeared for i=1-5 and only a monotropic nematic phase was observed for i=6-9. The mesomorphic potential is relatively weaker for the 1a-i than for the 2a-i and 3a-i homologues, which are pyridine-containing three- and four-ring similar systems. This lowering of the mesogenicity may be due to the lack of a phenyl ring between the pyridine ring and the methyl group in the 1a-i homologues.     

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.     

Preparation and Absolute Configuration of Some Iris Essential Oil Constituents of the 5-methylsafranic-acid series

The β-dienoate (+)-(5S)- 13a (86% ee; meaning of α and β as in α- and β-irone, resp.) was obtained from (?)-(5S)- 9a via acid-catalyzed dehydration of the diastereoisomer mixture of allylic tertiary alcohols (+)-(1S,5S)- 15 /(+)-(1R,5S)- 15 (Scheme 3). Prolonged treatment gave clean isomerization via a [1,5]-H shift to the α-isomer (?)-(R)- 16a with only slight racemization (76% ee; Scheme 4). In contrast, the SnCl₄-catalyzed stereospecific cyclization of (+)-(Z)- 6 to (?)-trans- 8a (Scheme 2), followed by a diastereoselective epoxidation to (+)- 11 gave, via acid-catalyzed dehydration of the intermediate allylic secondary alcohol (?)- 12 , the same ester (+)- 13a (Scheme 3), but with poor optical purity (13% ee), due to an initial rapid [1,2]-H shift. The absolute configuration of (?)- 16a–c was confirmed by chemical correlation with (?)-trans- 19 (Scheme 4). ¹³C-NMR Assignments and absolute configurations of the intermediate esters, acids, aldehydes, and alcohols are presented.     

Preparation and Absolute Configuration of (−)-(E)-α-trans-Bergamotenone

The synthesis, absolute configuration, and olfactive evaluation of (?)-(E)-α-trans-bergamotenone (= (?)-(1′S,6′R,E)-5-(2′,6′-dimethylbicyclo[3.1.1]hept-2′-en-6′-yl)pent-3-en-2-one; (?)- 1 ), as well as its homologue (?)- 19 are reperted. The previously arbitrarily attributed absolute configuration of 1 and of (?)-α-trans-bergamotene (= (?)-(1 S,6R)-2,6-dimethyl-6-(4-methylpent-3-enyl)bicyclo[3.1. 1]hept-2-ene; (?)- 2 ), together with those of the structurally related aldehydes (?)- 3a,b and alcohols (?)- 4a,b , have been rigorously assigned.     

Synthesis and characterization of trans-di(nitrobenzo)- and di(aminobenzo)-18-crown-6 derivatives with high selectivity

The dibenzo-18-crown-6 derivatives such as di(nitrobenzo)-18-crown-6 and di(aminobenzo)-18-crown-6 were synthesized by nitration reaction and catalytic hydrogenation with high selectivity. The chemical structures were determined by FTIR, ¹H NMR, ¹³C NMR, and UV. Regarding the mixture of Ac₂O and HNO₃ as nitrating agent, the reaction exhibited commendable trans-isomer selectivity. Effects of nitrating agent ratio, reaction temperature and reaction time on yield of trans-di(nitrobenzo)-18-crown-6 were investigated. The yield of trans-di(nitrobenzo)-18-crown-6 was 62.9% for nitrating agent ratio of 1/1, reaction temperature of 50?°C and reaction time of 5?h. Moreover, effect of reaction time on trans-di(aminobenzo)-18-crown-6 was also studied.     

Proof of the Absolute Configuration of (−)-(S)-2-Hydroxy-β-ionone by correlation with ursolic acid and with (−)-trans-verbenol

(?)-(S)-2-Hydroxy-β-ionone ( 33 ), (+)-(2 S, 6 S)-2-hydroxy-α-ionone ( 34 ), and their acetates 35 and 36 have been synthesized from (+)-(S)-6-methylbicyclo [4.3.0]-non-1-ene-3, 7-dione ( 3 ). The key intermediate (+)-(1 R, 3 S, 6 S)-2, 2, 6-trimethyl-7-oxobicyclo [4.3.0]non-3-yl acetate ( 7 ) was correlated with a degradation product of the pentacyclic triterpene ursolic acid ( 16 ). Compound 33 was also synthesized by an alternative route starting from (?)-trans-verbenol ( 42 ).     

Synthesis of(+)-(2S, 6S)-trans-α-Irone and of(-)-(2S, 6S)-trans-γ-Irone

A 3:1 mixture of (+)-(2S, 6S)-trans-α-irone ((+)-1) and (?)-(2S, 6S)-trans-γ-irone (?)-2) has been synthesized with ca. 70% e. e. by the ene reaction of (?)-(S)-3 and but-3-yn-2-one.     

Sesquiterpenoids from Costus Root Oil (Saussurea lappa CLARKE)

Apart from the well-known constituents (+)-β-selinene ( 2 ), (?)-β-elemene ( 4 ), (+)-β-costol ( 7 ), (?)-caryophyllene ( 17 ), and (?)-elemol ( 19 ) the following sesquiterpenoids have been isolated for the first time from costus root oil (Saussurea lappa CLARKE ): (?)-α-selinene ( 1 ), (+)-selina-4, 11-diene ( 3 ), (?)-α-trans-bergamotene ( 5 ), (?)-α-costol ( 6 ), (+)-γ-costol ( 8 ), (?)-elema-1,3,11 (13)-trien-12-ol ( 9 ), (?)-α-costal ( 11 ), (+)-γ-costal ( 12 ), (+)-γ-costal ( 13 ), (?)-elema-1,3,11 (13)-trien-12-al (elemenal, 14 ), (?)-(E)-trans-bergamota-2, 12-dien-14-al ( 15 ), (?)-ar-curcumene ( 16 ), and (?)-caryophyllene oxide ( 18 ). Compounds 6 , 8 , 9 , and 13 are new sesquiterpenoids. IR. and NMR. spectra of 12 sesquiterpenoids are reproduced.     

Preparation of optically active flowery and woody-like odorant ketones via Corey-Chaykovsky oxiranylation: Irones and analogues

α-, β-, and γ-Irones and analogues have been prepared from optically active ketones (+)- 1 , (+)- 6a,b , and (+)- 17 , via a Corey-Chaykovsky oxiranylation (Me₂S, Me₂SO₄, Me₂SO, NaOH) followed by isomerisation (SnCl₄ or MgBr₂). (+)-Dihydrocyclocitral ( 19a ), obtained from (?)-citronellal, and analogue (+)- 19b , were condensed with various ketones to afford (+)- 21a–f , and after hydrogenation (+)- 22a–f. A mild oxidative degradation of aldehydes (+)-trans-and (?)-cis- 8a,b , to ketones (?)- 16a,b , as well as olfactive evaluations, ¹³C-NMR assignments, and absolute configurations of the intermediate epoxides, aldehydes, and alcohols are presented.     

Stereochemical applications of mass spectrometry. 3—Energy dependence of the fragmentation of stereoisomeric methylcyclohexanols

Breakdown graphs have been constructed from charge exchange data for the epimeric 2-methyl-, 3-methyl- and 4-methyl-cyclohexanols. Although the breakdown graphs for epimeric pairs are essentially identical above ～12 eV recombination energy, significant differences are observed for the epimeric 2-methyl- and 4-methyl-cyclohexanols at low internal energies. For the 2-methylcyclohexanols the ratio ([M? H₂O]^+·/[M]^+·)_cis/([M? H₂O]^+·/[M]^+·)_trans is 3.2 in the [C₆F₆]^+· charge exchange mass spectra. This is attributed to both energetic and conformational effects which favour the stereospecific cis-1,4-H₂O elimination for the cis epimer. The breakdown graph for trans-4-methylcyclohexanol shows a sharp peak in the abundance of the [M? H₂O]^+· ion at ～10 eV recombination energy which is absent from the breakdown graph for the cis epimer. This peak is attributed to the stereospecific cis-1,4-elimination of water from the molecular ion of the trans isomer; the reaction appears to have a low critical energy but a very unfavourable frequency factor, and alternative modes of water loss common to both epimers are observed at higher energies. As a result, in the [C₆F₆]^+· charge exchange mass spectra the ([M? H₂O]^+·/[M]^+·)_trans/([M? H₂O]^+·/[M]^+·)_cis ratio is ～24, compared to the value of 13 observed in the 70 eV EI mass spectra. No differences are observed in either the metastable ion abundances or the associated kinetic energy releases for epimeric molecules.     

Hot Water‐Promoted SN1 Solvolysis Reactions of Allylic and Benzylic Alcohols

During the studies of hydrolysis of epoxides in water, we found that the hydrolysis of (?)‐α‐pinene oxide at 20 °C gave enantiomerically pure trans‐(?)‐sobrerol, whereas the same reaction in water heated at reflux unexpectedly gave a racemic mixture of trans‐ and cis‐sobrerol (trans/cis=6:4). We have examined this remarkable difference in detail and found that hot water, whose behavior is quite different compared with room‐ or high‐temperature water, could promote S_N1 solvolysis reactions of allylic alcohols and thus caused the racemization of trans‐(?)‐sobrerol. The effect of reaction temperature, the addition of organic co‐solvent, and the concentration of the solute on the rate of the racemization of trans‐(?)‐sobrerol were further examined to understand the role that hot water played in the reaction. It was proposed that the catalytic effects of hot water are owing to its mild acidic characteristic, thermal activation, high ionizing power, and better solubility of organic reactant. Further investigation showed that the racemization of other chiral allylic/benzylic alcohols could efficiently proceed in hot water.     

Enzyme-Mediated Preparation of (+)- and (–)-cis-α-Irone and (+)- and (–)-trans-α-Irone

The preparation of (−)- and (+)-trans-α-irone ( 1a and 1b , resp.) and of (+)- and (−)-cis-α-irone ( 1c and 1d , resp.) from commercially available Irone alpha ^® is reported. The relevant step in the synthetic sequence is the initial chromatographic separation of crystalline (±)-4,5-epoxy-4,5-dihydro-cis-α-irone ((±)- 5 ) from oily (±)-4,5-epoxy-4,5-dihydro-trans-α-irone ((±)- 4 ). The latter was subsequently converted, after NaBH₄ reduction, into the crystalline 3,5-dinitrobenzoate ester (±)- 8 , thus allowing a complete separation of the two corresponding diastereoisomeric alcohol derivatives. Suitable enantiomerically pure precursors of the desired products 1a – d were obtained by kinetic resolution of the racemic allylic alcohols derived from (±)- 5 and (±)- 8 , mediated by lipase PS (Amano). The last steps consisted of MnO₂ oxidation and removal of the epoxy moiety with Me₃SiCl/NaI in MeCN. External panel olfactory evaluation showed that (−)-cis-α-irone ( 1d ) has the finest and most distinct `orris butter' character.     

Die Geometrie des aktivierten Komplexes der thermischen und ladungsinduzierten aromatischen para → ortho - Claisen-Umlagerung

Pure 10β-(trans-2′-butenyl)-17β-hydroxy-estra-1,4-dien-3-one ( 6 ), 10-(trans-2′-butenyl)-2-oxo-Δ^1(9),3(4)-hexahydronaphthalene ( 13 ), trans-2′-butenyl 17β-hydroxy-3-estra-1,3,5-(10)-trienyl ether ( 12 ) and trans-2′-butenyl 5,6,7,8-tetrahydro-2-naphthyl ether ( 14 ) were prepared by direct C- and O-alkylation, respectively, of the corresponding phenols (cf. [3] [10]), namely estra-3, 17β-diol and 5,6,7,8-tetrahydro-2-naphthol. The Claisen rearrangement of the ether 14 (200°, 12 h) yielded 53% 1-(1′-methylallyl)- and 34% 3-(1′-methylallyl)-5,6,7,8-tetrahydro-2-naphthol ( 15 and 16 , respectively), whereas in the thermal (120°, 14 h) and in the acid-catalysed (boron trifluoride in ether, 20°, 20 min) reaction of the corresponding dienone 13 nearly equal amounts of 15 (53–54%) and 16 (46%) were formed by thermal and charge-induced aromatic [3s, 3s]-sigmatropic rearrangements [2]. The steroid dienone 6 , on heating at 120°, was rearranged by [3s, 3s]-sigmatropic processes to form 52% of 2-(1′-methylallyl)- and 48% of 4′-(1′-methylallyl)-3, 17β-dihydroxy-estra-1,3,5,(10)-triene ( 7 and 8 , respectively). The steroid phenols 7 and 8 were carefully separated; subsequent hydrogenation (Raney-Ni in alcohol) and ozonolysis yielded 2-methylbutyric acid ( 9 ): from 7 , S-(+)- 9 , and from 8 , R-(?)- 9 , obtained in 88,5 and 88,0% optical purity (cf. [4a]). This means (cf. scheme 2 and Table 2) that both phenols are formed to the extent of at least 94% via a chair-like activated complex, and of at most 6% via a both-like activated complex (ΔΔG = 2.15 kcal/mol). Similarly, the boron trifluoride-induced rearrangement of 6 (born trifluoride in ether, 0°, 45 min) yielded 7 and 8 , from which S-(+)- 9 and R-(?)- 9 were respectively obtained in 89% and 98% optical purity. For these induced rearrangements this corresponds to at least 94,5 and 99%, respectively, of the chair-like, and to only 5.5 and 1% of the boat-like activated complex (ΔΔG = 1.5–2.5 kcal/mol). These results demonstrate that the activated complexes of both [3s,3s]-sigmatropic processes, i.e. the pure thermal reaction at 120° and the charge-induced reaction occurring at 0°, must be very similar. Thus, the boron trifluoride accelerates the Cope-like reactions 6 → 7 + 8 , but does not influence the geometries of their transition states. The Claisen rearrangement of the steroid ether 12 (200°, 15 h), yielding 7 and 8 , was not influenced by the chiral steroid skeleton, because no optical induction was observed (both phenols, 7 and 8 , yielded on degradation racemic 2-methylbutyric acid (9)).