Neighbouring group participation in the reaction of 7-oxo-ent-kaur-16-ene derivatives with diacetoxyiodobenzene. Synthesis of gibberellin analogues

The reaction of different 7-oxo-ent-kaur-16-ene derivatives with diacetoxyiodobenzene has been evaluated for the preparation of gibberellin analogues. Thus, the reaction of 7-oxo-ent-kaur-16-en-18-oic acid methyl ester (3) with this reagent afforded 4-epi-GA₁₂ dimethyl ester (6). This reaction constitutes a good procedure for the preparation of this type of compounds. In some cases, alternative reactions that led to the introduction in the substrate of a conjugated 5,6-double bond or to the formation of a ketal at the 6-position were also produced. The formation of these compounds, or of gibberellin analogues, depends on the neighbouring group participation of the different C-18 and C-19 substituents at C-4.     

Gibberellin metabolites from ent-kaura-2,16-dien-19-ol and its succinate in Gibberella fujikuroi

Exposure of ent-kaura-2,16-dien-19-ol (1) or its succinate (2) to resuspended mycelia of G. fujikuroi has produced a complex mixture of acids which after methylation gave the esters of two C₁₉ (24) and (30) and five C₂₀ gibberellins (4, 11, 20, 32 and 33). The triester (32) and the lactone ester (24) have been prepared before from the esters of gibberellin A₁₃ (8) and gibberellin A₄ (26) respectively. The structures of the other metabolites were assigned on spectroscopic data and by chemical transformations. Thus the lactone diester (4) has been converted to the known keto triester (6). The epoxide (11) has been related to gibberellin A₁₄ (14) and the aldehyde (33) has been related to gibberellin A₁₃ trimethyl ester (8) by way of the triol (34). Selective de-epoxidation of the 16,17-epoxy function in diepoxides has provided a route from the dienes (20 and 24) to the epoxides (11 and 30) respectively, but not from the ester of gibberellin A₅ (23) to that of gibberellin A₆ (29). On the other hand the latter can be obtained by epoxidation of gibberellin A₅ methyl ester trifluoroacetate. Backfeeding experiments carried out with the epoxy diacid (12), the diene diacid (21) and the derived diol (39) indicate pathways connecting the various metabolites. The natural gibberellins A₅ and A₆ were shown to be formed in some of the backfeeding experiments.     

Vilmoraconitine, a novel skeleton C19-diterpenoid alkaloid from Aconitum vilmorinianum

A novel C₁₉-diterpenoid alkaloid vilmoraconitine (1) was isolated from the roots of Aconitun vilmorinianum. Its structure was mainly determined by MS, 2D NMR, and X-ray methods. This is the first aconitine-type C₁₉-diterpenoid alkaloid with one three-membered ring at C-8, C-9, and C-10.     

The biosynthetic origin of fusicoccin hydroxyisopropyl group

The biosynthetic origin of the hydroxyisopropyl group of fusicoccin 1 has been determined. Two out of the eight tritium mevalonoid atoms retained in 1 following incorporation of MVA-[2-³H₂,2-¹⁴C] have been located at C-20; whilst none has been found in the C-19 methylene group.     

New reactivities of deltaline analogs: an efficient O-demethylation at C-1 and an unusual extrusion of the C-14 atom

O-Demethylation at C-1 in the C₁₉-diterpenoid alkaloids is very challenging. In this paper, it was firstly observed that 10-OH group in deltaline (1) is a determining factor for the O-demethylation reaction. After removal of this hydroxyl group, 1-O-methyl group in the corresponding deltaline analogs can be readily removed by treatment with HBr–HOAc. Meanwhile, the C-14 atom in bromides 18 or 20 can be extruded under basic condition probably via a sequence, including Grob fragmentation, aerobic oxidation, deformylation, and S_N2 nucleophilic substitution, to give enone 21 (70%) and oxetane 22 (14%). The structure of compound 22 was confirmed by X-ray crystallographic analysis of its derivative 21.     

Novel 3,4- and 8,15-polyether analogues of macrocyclic trichothecenes

Protecting group chemistry on derivatives of T-2 toxin (2) involving silylation (TBDMS ethers) of the hydroxyl groups at C-3 and C-4, and acetalation (benzylidene acetals) of the C-8 and C-15 hydroxyl groups, has afforded the 3,4- and 8,15-polyether analogues 9–12 and 18 and 19 of macrocyclic trichothecenes.     

Photochemische reaktionen—XXV : Photochemische synthese von ring A-annelierten gibberellinen der GA1-reihe

The photochemical [2 + 2]-cycloaddition of ethylene and tetramethylethylene to 3-dehydro gibberellin A₃ (1) under n → π^*-excitation conditions has been investigated. The reaction leads to a 3 : 1 ratio of the cis-fused α- and β-cyclobutane annelated epimers 3 and 5 as well as 18 and 20 in 70 and 86% yield, respectively, besides small amounts of the phenolic acid 22 and dimeric material. NaBH₄-reduction of 3 gives stereospecifically the 3α-hydroxy compound 7 whereas the 1β,2β-epimer 5 yields the corresponding ring A annelated gibberellin A₁ analogues 12 and 16 in a 6:1 ratio. The constitution and stereochemistry of the products are deduced by physical methods and some mechanistical aspects discussed on the basis of qualitative quenching experiments.     

Gibberelline—lxii: Synthese von 7-desoxygenierten gibberellin-a3-verbindungen

Reaction sequences leading to GA₃ derivatives with stepwise deoxygenated position 7 have been reported. From four different methods studied for the synthesis of GA₃-7-alcohols the direct NaBH₄-reduction of the anhydrides5a and5b has been found to be optimal leading in good yields to 3 and 9, respectively. Oxidation of 3 with the N - chlorosuccinimide - dimethylsulfide complex or pyridinium chlorochromate followed by deacetylation afforded the GA₃-7-aldehyde 16.—The partial synthesis of 6β-methyl-7-nor-GA₃20 has been realized starting from 3 via the iodinemethyl compound 18 and its reduction with (C₂H₅)₃SnH or Na₂[Fe(CO)₄] to19 and subsequent saponification.—The structures of the new gibberellin derivatives were determined on the basis ofIR, ¹H-NMR and MS data.     

Addition of 2-tert-butyldimethylsilyloxythiophene to activated quinones: an approach to thia analogues of kalafungin

The uncatalyzed reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-quinones bearing either an electron withdrawing acetyl or a carbomethoxy group at C-2, was investigated. No reaction was observed using 1,4-quinones 8 and 9 bearing an ester group at C-2 whereas use of 1,4-quinones 10 and 11 bearing an acetyl group at C-2 only provided low yields of the silyloxythiophenes 15 and 16 resulting from electrophilic substitution of the silyloxythiophene by the 1,4-quinone. Use of the Lewis acids InCl₃, Cu(OTf)₂ and BF₃·Et₂O were investigated in an effort to improve the yield of the desired annulation reaction. BF₃·Et₂O proved to be the optimum catalyst for the synthesis of thiolactone naphthofuran adducts 14 and 18 from 1,4-naphthoquinones 9 and 11, respectively. Reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-benzoquinones 8 and 10 bearing a carbomethoxy or an acetyl group at C-2, respectively, afforded thiolactone benzofuran adducts 13 and 17, respectively, catalyzed by either InCl₃ or Cu(OTf)₂. Addition of 2-tert-butyldimethylsilyloxythiophene 2 to 3-acetyl-5-methoxy-1,4-naphthoquinone 12 afforded adduct 19 that underwent oxidative rearrangement to thiolactone pyranonaphthoquinone 20 using ceric ammonium nitrate in acetonitrile, thus providing a novel approach for the synthesis of a thia analogue of the pyranonaphthoquinone antibiotic kalafungin.     

1,4-Dihydropyridine/BF3OEt2 for the reduction of imines: Influences of the amount of added BF3OEt2 and the substitution at N-1 and C-4 of the dihydropyridine ring

We have evaluated four 1,4-dihydropyridines (DHPs 1a, 1b, 1c and 1d) as reducing agents, which presented free (hydrogenated) or phenyl-substituted N-1 and C-4 positions of the DHP ring. Reactions combining each of the DHP and different amounts of BF₃OEt₂ were evaluated for the reduction of imine 2a (N-benzylideneaniline). DHP simultaneously substituted at N-1 and C-4 (1a), and DHP substituted at C-4 (1b) gave lower yields for reduction of 2a in comparison with DHPs 1c and 1d (both unsubstituted at the C-4 position). By evaluating the amount of added BF₃OEt₂ to the reaction mixture, we have found that DHP 1c (substituted at N-1) provided its best yield for amine 3a (82%) when associated with stoichiometric amounts BF₃OEt₂, while DHP 1d (N-1- and C-4-unsubstituted derivative) was more effective (90% yield) with catalytic quantities of the Lewis acid. The reaction system using DHP 1c under stoichiometric BF₃OEt₂ could also be successfully applied with additional imine examples and under reductive amination conditions.     

Preparation of 2,2′-anhydronucleosides: regio- and stereoselective modifications of the base and sugar moieties

2′-Deoxy-2′-iodonucleosides 4–9, obtained from suitably protected furanoid glycals 1 and 2 with different silylated pyrimidine bases, were transformed into the corresponding 2,2′-anhydronucleosides 10–15 with inversion of the configuration at C-2′, by heating in DMF with n-dibutyltin oxide. Regio- and stereospecific opening at C-2′ of the 2,2′-ring in compounds 10, 11, and 12 with sodium azide afforded the related 2′-azido-2′-deoxynucleosides 16, 17 and 18, respectively. Action of sodium hydroxide on 12 caused the regioselective opening of the above-mentioned ring at C-2 with retention of the configuration at C-2′ giving 19. Compound 19 could be transformed straightforwardly into 18 by well-established methodology. On the other hand, compound 15 could be transformed into the related 2′,3′-anhydronucleoside 23 by a regio- and stereoselective addition at N-3–C-2′ of allyl bromide concomitant with 2,2′-ring opening and inversion of the configuration at C-2′ to afford the intermediate 2′-bromo-2′-deoxynucleoside 21, which was subsequently treated with sodium methoxide giving 23.     

Alcaloïdes indoliques—CIII: Préparation de dérivés de l'hétéroyohimbane à partir de la corynanthéine. Réactivité de l'enchaînement MeOOC-CHCHOR vis-à-vis de la double liaison vinylique activée par mercuration

The reactivity of the MeOOC-CHCHOR group (R = H or Me) or demethyl-corynantheine 1 and corynantheine 26 towards the vinylic double bond activated by mercuration is studied. In the presence of Hg(OAc)₂ in warm AcOH the mercurinium ion derived from 1 undergoes both a non-stereoselective Markovnikov attack by the enolic oxygen and an anti-Markovnikov attack by the activated C-16 methine leading to a mixture of 2a,3a and 4a after demercuration. In the presence of Hg(OCOCF₃)₂ in aq THF or MeOH, 1 gives mainly ,19α-H cyclic hemiketals and ketals. It is assumed that the stereoselectivity of the reaction is due to the formation of the intermediate oxonium 25 leading to the more stable epimer. In the same conditions (aq THF) 26 reacts as a hemiketal MeOOC-CH₂CH(OH)OMe affording essentially a mixture of cyclic ketals. These ketals, on treatment with PPA, give ajmalicine 2a and 19-épiajmalicine 3a.     

Structure and absolute stereochemistry of 19-epi-(+)-echitoveniline : A new indole alkaloid of the leaves of Alstonia venenata r.br.

19-Epi-(+)-echitoveniline, a new indole alkaloid of the leaves ofAlstonia venenata R.Br., has been shown to possess the structure and absolute stereochemistry represented by 5b on the basis of spectral and chemical evidence. A mechanistic rationale for the dependence of the mode of LAH reduction of the δ-lactone 11 on its configuration at C-19 has been offered. The influence of the C-19 configuration on the chemical shift values of the C-16 carbomethoxy protons in the 19-aroyloxy-(+)-and (?)-vincadifformine alkaloids has been discussed.     

Photochemische reaktionen—XXXII: Photochemie von gibberellin C; wege zur funktionalisierung von gibbanen in position 8 und 11

The n→π^* photochemistry of saturated diterpenoid ketones of the gibberellin C type 1 has been investigated. A Norrish type 1 cleavage leading to Δ⁷⁽¹¹⁾-unsaturated 7,8-seco-8-aldehydes 5 and 6, respectively, takes place as the main process. These secoaldehydes upon prolonged irradiation undergo intramolecular “crossed” photocycloaddition to the highly strained oxetanes 7 and 8. The oxetane methylester 8 represents a suitable key compound for proton catalyzed ring opening reactions under nucleophilic attack at C-8. In such a manner a series of 8α,11α-bifunctionalized gibbanes 12–20 have been prepared in good yields and under mild conditions.     

Méthylène-indolines,indolénines et indoléniniums—XIII: L'hydroxy-16 déhydro-1 vincadifformine,intérmédiaire dans le réarrangement biomimétique de la vincadifformine en vincamine

The title compound is a crucial intermediate in the biomimetic conversion of vincadifformine 1 into vincamine 7. Its configuration at C-16 is established by a combination of chemical and spectroscopic evidence. Iodine oxidation converts 14 into the bridged lactam 18, thus proving a β configuration for the hydroxy group at C-16. The same reaction applied to vindoline 19 gives 21 identical with one of the compounds obtained by microbiological transformation of 19. The ¹³C NMR spectra of derivatives 3 and 8 (obtained by oxidation of vincadifformine) show that oxidation proceeds with introduction of the substituent at C-16, with a β-configuration. The alcohol 3 however, posesses a different conformation due to strong hydrogen bonding with N-4.     

Stereochemische untersuchungen an C-10-disubstituierten C-9-hydroxyphäophorbiden der a-reihe

The diastereomeric 9-hydroxy pheophorbides 3a, b-1, 2 and 4a, b-1, 2 were prepared by reduction of the 10-alkoxy pheophorbides 1a, b and 2a, b with NaBH₄. Their absolute configuration at C-10 was determined by NMR- and ORD/CD-measurements as well as chemical correlation, the configuration at C-9 by IR- and mainly NMR-spectroscopy. For this purpose, the NMR-spectra of the 9-hydroxy pheophorbides 3a, b-1, 2 had completely to be assigned with the aid of the selectively deuterated alcohols 5a, b-1, 2. The configuration at C-10 is stable under the conditions of the alkaline reduction while C-9 partially epimerizes. The acidic alcoholysis of 3a, b-1, 2, however, proceeds by equilibration at C-10 and almost complete retention at C-9. The H-bonds between the 9-OH group and the C-10 substituents (-COOCH₃, -OCH₃ were investigated by NMR and IR spectroscopy.     

New compounds from the roots of Coriaria nepalensis

One new sesquiterpene lactone possessing novel variations in the structure, corialactone E (1), one new neolignan, coriarianeolignan A (2), together with three known apocarotenoids (3-5) and one known neolignan (6), have been isolated from a CHCl₃ extract of the roots of Coriaria nepalensis.     

Mycopyranone: A 8,8ˈ-binaphthopyranone with potent anti-MRSA activity from the fungus Phialemoniopsis sp.

A new 8,8?-binaphthopyranone (mycopyranone, 1) was isolated from a solid fermentation of Phialemoniopsis sp. (fungal strain MSX61662), and the structure was elucidated via analysis of the NMR and HRESIMS data. The axial chirality of 1 was determined to be M by ECD. The central chirality at C-4/C-4? was assigned through a modified Mosher’s method, while the absolute configuration at C-3/C-3? was deduced based on analysis of the ³J_H-3-H-4 values and NOESY correlations. Compound 1 was evaluated for its antimicrobial properties against Staphylococcus aureus SA1199 and a clinically relevant methicillin-resistant S. aureus strain (MRSA USA300 LAC strain AH1263). Compound 1 inhibited the growth of both strains in a concentration dependent manner with IC₅₀ values in the low μM range. Molecular docking indicated that compound 1 binds to the FtsZ (tubulin-like) protein in the same pocket as viriditoxin (2), suggesting that 1 targets bacterial cell division.     

Artanomadimers A–F: six new dimeric guaianolides from Artemisia anomala

A novel dimeric guaianolide with an unprecedented skeleton, named artanomadimer A (1), and five new analogues, artanomadimers B–F (2–6), were isolated from the aerial parts of Artemisia anomala. Their structures and stereochemistry were elucidated by extensive spectroscopic methods, and the absolute stereochemistry of compound 4 was confirmed by X-ray crystallographic analysis. Artanomadimer A (1) is probably formed through a Diels–Alder reaction with the new carbon–carbon bond formation of C-11/C-2′ and C-13/C-5′ based on its structure. A cytotoxic evaluation showed that compounds 1 and 6 exhibited significant inhibitory effects against the cell growth of BGC-823 tumor cell lines with IC₅₀ values of 2.71 and 6.25 μM, respectively.     

The stereospecificity and stereoselectivity of hydrogen transfer in photochemical reactions

The photolysis of methyl ent-19-acetoxy-3-oxo-beyer-15-en-17-oate (3) occurs with retention of configuration of C-4 to give the 4S-3,4-seco acid. In the phototransformation of 3-ketobeyeranes to 3,4-seco acids the C-2 axial hydrogen is transferred preferentially to C-4.