Reaction of quinidine acetate, epiquinidine and its acetate in superacid: formation of gem-difluoro derivatives with or without rearrangement

In HF-SbF₅, quinidine 1a or its dihydrochloride cyclises previously obtained with usual acids. A similar reaction is observed in the presence of CCl₄. Under similar conditions quinidine acetate 1b and epiquinidine acetate 2b dihydrochlorides both yield 10,10-difluoro derivatives epimeric at C-3, 6 and 7, and 9c and 10b, and a rearranged difluoro derivative 8b and 11b, respectively. Epiquinidine 2a leads to the expected analogues 10a and 11a and to a ketone 9a. Formation of gem-difluoro compounds implies chloro intermediates at C-10, precursors of α-chlorocarbenium ions, which are trapped by a fluoride ion and which lead by halogen exchange to the products.     

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.     

Specific oxidation of C-14 oxygenated 4(20),11-taxadienes by microbial transformation

Three C-14 oxygenated taxanes, 2α,5α,10β,14β-tetraacetoxytaxa-4(20),11-diene (1), 2α,5α,10β-triacetoxy-14β-(2-methylbutyryloxy)taxa-4(20),11-diene (2), and yunanaxane (3), major products of callus cultures of Taxus spp., were regio- and stereoselectively hydroxylated at the 7β position by a fungus, Absidia coerulea IFO 4011. Intriguingly, when 1 was co-administered with β-cyclodextrin and incubated with the fungus cell cultures, three other compounds 5α,9α,10β,13α-tetraacetoxytaxa-4(20),11-dien-14β-ol (7), 5α,9α,10β,13α-tetraacetoxytaxa-4(20),11-dien-1β-ol (8) and 5α,9α,10β,13α-tetraacetoxy-11(15→1) abeotaxa-4(20),11-dien-15-ol (9) were obtained.     

7-β- and 10-β-Hydroxylated congeners of CAF-603; elucidation of absolute configuration of CAF-603 family,and their SAR studies in the anti-fungal activity

Novel 7-β- and 10-β-hydroxylated congeners of CAF-603 (4 and 5, respectively) were isolated from Trichoderma crassum. Relative configuration of 4 was determined by NOE experiments. Stereochemistry of 7-β-hydroxy group in 5 was established by a combination of vicinal ³J_H–H analyses and quantum chemical calculations. Absolute configurations of 4 and 5 were established by observing the Cotton effects of their bis(2-naphthoate) esters. T. crassum also produce known CAF-603 (1), 14-hydroxy and 8,9-β-epoxy derivatives (2 and 3, respectively). Present study first established the absolute configuration of CAF-603 family by taking their biosyntheses into account. Preliminary biological experiments revealed that the molecular target strictly recognizes the β-side of the cycloheptane ring.     

Thermal rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates. Synthesis of 3H-imidazol-1-ium ylides and their silver derivatives

Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD undergo rearrangement to 3,4-dihydro-2H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides) 3, which spontaneously undergo elimination to give 3H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides) 5 or 1H-imidazoles 6 when heated in toluene at reflux. The presence of the aromatic ring at C-6 decelerated the conversion and enhanced the yield of 5. Solvents more polar than toluene (e.g., DMSO) provided quantitative conversion of 2 into 6 in mild conditions, while in less polar solvents such as CCl₄, the reaction rate was lowered and the yield of 5 enhanced. C-2 unsubstituted ylides 5 were treated with Ag₂O or AgNO₃ in the presence of Et₃N at room temperature to give C-2 metallated derivatives 9 in excellent yields.     

Withaphysanolide A, a novel C-27 norwithanolide skeleton, and other cytotoxic compounds from Physalis divericata

A novel C-27 norwithasteroid, withaphysanolide A (1) containing a pyran ring was isolated from the aerial parts of Physalis divericata. Four known withaphysalins (2-5) and five physalins (6-10) were also isolated. The structural assignment for 1 was done based on spectroscopic and single-crystal X-ray diffraction data. Logical biosynthetic pathways were postulated. Compounds 6, 7, and 10 displayed potent cytotoxic activity against HCT-116 and H460 human cancer cell lines, with IC₅₀ values less than 2.0 μM.     

Reaction of quinine, 9-epiquinine and their acetates in superacid in the presence of hydrogen peroxide: an access to new fluorhydrins and/or ketones

In HF-SbF₅, in the presence of H₂O₂ (source of OH⁺ equivalent) quinine 1a yields 10-keto derivatives 4a and 5a and cyclic ether 3 as the major product. In the same conditions 1b, 2a, and 2b give the 10-keto and 10-fluoro-3-hydroxy analogs.     

An efficient synthesis of diquinane-based bis-γ-lactones

An efficient stereoselective synthesis of both the diastereomers of diquinane-based conformationally constrained symmetric bis-γ-lactones starting from tricyclic derivative 9 is reported. The key step involves the intramolecular ring opening of an epoxide by the in situ formed hydrate of a diketone leading to the tetracyclic hemiacetal 10, which directly leads to the exo-hydroxy bis-γ-lactone derivatives 2 and 4 under basic hydrogen peroxide cleavage conditions. Conversion to the endo-hydroxy bis-γ-lactone derivatives 1 and 3 was accomplished through lithium hydroxide mediated S_N2 displacements in dimesylate 7, or more expeditiously, via trimesylate 21 through alkaline H₂O₂ mediated cleavage.     

Absolute stereochemistry of amphidinolide C: synthesis of C-1-C-10 and C-17-C-29 segments

Two of each diastereomers of the C-1-C-10 and C-17-C-29 segments of amphidinolide C (1) were synthesized. Comparing the ¹H NMR chemical shifts of its MTPA esters with those of linear methyl ester of 1, the absolute configurations at C-7, C-8, C-20, C-23, and C-24 in amphidinolide C (1) were confirmed to be all R.     

Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-, and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct C-5 arylation of 1-benzyl-1H-imidazole

Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5-diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds 3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed by N-debenzylation.     

Synthesis, structural and conformational studies of Z- and E-isomers of fluorinated C-6 isobutenyl N-methyl thymine derivatives

A new series of conformationally restricted pyrimidine derivatives bearing C-6 isobutenyl side-chain (2-9) has been prepared. The novel fluoroalkenyl pyrimidine nucleoside mimetic 3 as model compound for development of tracer molecule in positron emission tomography (PET) was synthesized by fluorination reaction of methoxytritylated pyrimidine derivative using diethylaminosulfur trifluoride (DAST). Conversion of one hydroxyl group to methoxytritylated, fluorinated, mesylated and acetylated pyrimidine derivatives (2, 3, 5-7 and 9) afforded a mixture of Z- and E-isomers in which Z-isomers were predominant. Conformational study of 1, and its fluorinated structural congeners 3 and 4 by the use of NOE experiments revealed predominant conformation of compounds where vinyl H-1′ proton is spatially close to N-1 methyl and H-3′b methylene protons and on the other hand H-3′a methylene protons are close to C-5 methyl protons. The stereostructure of 1,3-dihydroxyisobutenyl N-methyl thymine 1 was unambiguously confirmed by X-ray crystal structure analysis.     

5′-Noraristeromycin possessing a C-1′ cyclopentyl double bond: a new carbanucleoside structural prototype

Prior to this work only two examples of carbanucleosides possessing a C-1′/C-6′ double bond had been reported and they were minor derivatized side products arising during other targeted syntheses. To develop this structural feature into a new class of potential antiviral agents, the 5′-nor derivative of aristeromycin with such an olefinic structure (6) represents the first example. In this regard, treatment of (1′S,2′S,3′S,4′R,5′S)-6-chloro-9-(2′,3′-isopropylidenedioxy-6′-oxabicyclo[3.1.0]hex-4′-yl)purine (7) with sodium methoxide yielded 6 via an E′₂-like elimination pathway. A convenient way to the C-4′ epimer of 6 (that is, 17) also arose during these studies and is described. Antiviral analysis of 6 and 17 failed to produce any significant activity.     

Synthesis of all the six components of the female-produced contact sex pheromone of the German cockroach, Blattella germanica (L.)

All of the following six components of the female sex pheromone of the German cockroach, Blattella germanica (L.) were synthesized: (3S,11S)-3,11-dimethyl-2-nonacosanone (1), its 29-hydroxy derivative 2, its 29-oxo derivative 3, (3S,11S)-3,11-dimethyl-2-heptacosanone (4), its 27-hydroxy derivative 5, and its 27-oxo derivative 6. Both the enantiomers of citronellal were employed as the chiral sources and Wacker oxidation was employed for the introduction of the carbonyl group at C-2.     

On the C-2 epimerisation of kainoids

The conditions for the epimerisation at carbon C-2 of phenyl kainic acid esters 6 and 7 and cis-3-prolinoglutamic esters 10 were systematically addressed. We found that the use of KHMDS in THF gave improved results over the existing procedures. Some mechanistic aspects of this peculiar epimerisation are discussed.     

Two unprecedented cembrene-type terpenes from an indonesian soft coral sarcophyton sp.

Two unusual cembranoids, sarcofuranocembrenolides A (1) and B (2), were isolated from a soft coral Sarcophyton sp. together with five known cembranoids (3-7). Compound 1 had a unique carbon skeleton of 8,19-bisnorfuranocembrenolide. Compound 2 was a furanocembrenolide, but a C₁ unit (C-20) was attached to C-10 instead of C-12 of the ordinary cembrenolides. These rearrangements are unique in the biosynthesis of cembranoid diterpenes. Lobohedleolide (5), (7Z)-lobohedleolide (6), and denticulatolide (7) inhibited the colony formation of V79 cells at ED₅₀ values of 4.6 (abt. 1.52), 3.7 (1.22), and 3.6 (1.40) μM (μg/mL), respectively, and reduced TNF-α production from LPS-stimulated RAW264.7 cells at 3.0-10.0 μM.     

Synthesis of pyrrolo[3,2-b]benzofurans and pyrrolo[3,2-b]naphthofurans via addition of a silyloxypyrrole to activated quinones

The uncatalyzed reaction of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 with 1,4-quinones bearing an electron withdrawing group at C-2 has been studied. Use of 1,4-quinones 4, 5 bearing an ester group at C-2 provided an efficient synthesis of the respective pyrrolidinobenzofuran adduct 9 or pyrrolidinonaphthofuran adduct 10 whereas use of 1,4-quinones 6, 7 and 8 bearing an acetyl group at C-2 afforded silyloxypyrroles 11, 12 and 13 resulting from direct electrophilic substitution of the silyloxypyrrole by the electrophilic quinone. Addition of Eu(fod)₃ to the reaction of 2-acetyl-1,4-naphthoquinone 7 and 3-acetyl-5-methoxy-1,4-naphthoquinone 8 with N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 provided a method for obtaining the pyrrolidinonaphthofuran adducts 14 and 15 together with silyloxypyrroles 12 and 13. Oxidative rearrangement of pyrrolidinonaphthofuran adduct 15 to pyrrolidino pyranonaphthoquinone 16 using ceric ammonium nitrate in acetonitrile provided a novel approach for the synthesis of an aza-analogue of the pyranonaphthoquinone antibiotic kalafungin.     

Sodium dithionite initiated addition of 1-bromo-1-chloro-2,2,2-trifluoroethane to β-pinene: Synthesis of CF3-substituted terpenoids

Sodium dithionite effectively promotes the addition of 1-bromo-1-chloro-2,2,2-trifluoroethane to the exocyclic double bond of β-pinene. The reaction proceeded in an MeCN/H₂O system to give almost quantitatively a 1:1 mixture of diastereoisomers of 4-(2-bromoisopropyl)-1-(2-chloro-3,3,3-trifluoropropyl)-cyclohexene (1). Dehydrobromination of 1 with pyridine gave a mixture of regioisomeric dienes 2 and 3, while treatment with DBU at elevated temperature resulted in total dehydrohalogenation to give trienes 4 and 5. Reduction of 1 with Bu₃SnH gave 1-(2-chloro-3,3,3-trifluoropropyl)-4-(isopropyl)cyclohexene (6) which on dehydrochlorination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) afforded conjugated diene, 4-isopropyl-1-(trans-3,3,3-trifluoropropenyl)-cyclohexene (7), with 50% overall yield. All the transformations proceeded with the retention of configuration at the carbon atom C-4 and the final compound 7 exhibited high optical activity.     

Structural and spectroscopic characteristics of two new dibenzylbutane type lignans from Taxus baccata L.

Chromatographic separation of chloroform extracts of the heartwood of Taxus baccata L. has yielded two new dibenzylbutane type lignans, together with a known lignan. Their structures were established as 3′-demethylisolariciresinol-9′-hydroxy isopropylether (1) and 3-demethylisolariciresinol (2) and isolariciresinol (3) on the basis of 1D- and 2D-NMR spectroscopic analysis. Compounds 1 and 2 were identified as new lignans of isolariciresinol derivatives. Compound 1 is the first lignan with a hydroxyisopropyl group at C-9′. Molecular mechanic calculations of these compounds were carried out by using mm3 program. Furthermore, the conformations of these three compounds were computed with the semi-empirical molecular orbital methods AM1 and PM3 by using X-ray crystal structure results of similar compounds. So, three-dimensional, the most probable structure of these compounds were obtained, compared and discussed.     

Leptogorgolide, a biogenetically interesting 1,4-diketo-cembranoid that reinforces the oxidation profile of C-18 as taxonomical marker for octocorals

The cembranoid 1 and the furanocembranolides 2-4 along with the known pukalide were isolated from Leptogorgia sp. and their structures determined spectroscopically. The 1,4-diketo-cembranoid 1 follows an oxidation pattern of C-18 that reinforces the concept of oxidation profile of C-18 as taxonomical marker for octocorals. The co-occurrence within a species of furanocembranolide/1,4-diketo-cembranoid congeners 1/2-4 raises the question about which one is the biogenetic precursor. A biogenetic pathway is proposed.     

C-4′ Truncated carbocyclic formycin derivatives

Formycin is a naturally occurring C-glycoside (C-nucleoside) that possesses antitumor, antibacterial, antifungal, and antiviral activity. In connection with our ongoing interest in the design and syntheses of C-nucleoside derived antiviral agents this report describes the preparation of carbocyclic formycin and its 7-hydroxy (oxo) analog lacking the C-4′ hydroxylmethylene moiety in racemic form (4 and 6, respectively). An antiviral analysis of (±)-4 did not disclose any activity.