Synthesis and fate of o-carboxybenzophenones in the biosynthesis of aflatoxin

o-Carboxybenzophenones have long been postulated to be intermediates in the oxidative rearrangement of anthraquinone natural products to xanthones in vivo. Many of these Baeyer-Villiger-like cleavages are believed to be carried out by cytochrome P450 enzymes. In the biosynthesis of the fungal carcinogen, aflatoxin, six cytochromes P450 are encoded by the biosynthetic gene cluster. One of these, AflN, is known to be involved in the conversion of the anthraquinone versicolorin A (3) to the xanthone demethylsterigmatocystin (5) en route to the mycotoxin. An aryl deoxygenation, however, also takes place in this overall transformation and is proposed to be due to the requirement that an NADPH-dependent oxidoreductase, AflM, be active for this process to take place. What is known about other fungal anthraquinone --> xanthone conversions is reviewed, notably, the role of the o-carboxybenzophenone sulochrin (25) in geodin (26) biosynthesis. On the basis of mutagenesis experiments in the aflatoxin pathway and these biochemical precedents, total syntheses of a tetrahydroxy-o-carboxybenzophenone bearing a fused tetrahydrobisfuran and its 15-deoxy homologue are described. The key steps of the syntheses entail rearrangement of a 1,2-disubstituted alkene bearing an electron-rich benzene ring under Kikuchi conditions to give the 2-aryl aldehyde 43 followed by silyltriflate closure to a differentially protected dihydrobenzofuran 44. Regiospecific bromination, conversion to the substituted benzoic acid, and condensation with an o-bromobenzyl alcohol gave esters 47 and 50. The latter could be rearranged with strong base, oxidized, and deprotected to the desired o-carboxybenzophenones. These potential biosynthetic intermediates were examined in whole-cell and ground-cell experiments for their ability to support aflatoxin formation in the blocked mutant DIS-1, defective in its ability to synthesize the first intermediate in the pathway, norsolorinic acid. Against expectation, neither of these compounds was converted into aflatoxin under conditions where the anthraquinones versicolorin A and B readily afforded aflatoxins B1 and B2. This outcome is evaluated further in a companion paper appearing later in this journal.     

Synthesis of 11-hydroxyl O-methylsterigmatocystin and the role of a cytochrome P-450 in the final step of aflatoxin biosynthesis

The major skeletal rearrangements (anthraquinone --> xanthone --> coumarin) that occur in the complex biosynthesis of aflatoxin B(1) are mediated by cytochromes P-450. Previous experiments have suggested that two successive monooxygenase reactions are required to convert the xanthone O-methylsterigmatocystin (OMST) to aflatoxin, a process we demonstrate is mediated by a single P-450, OrdA, in Aspergillus parasiticus in accord with findings in A. flavus. The first oxidative cycle is proposed to result in the formation of 11-hydroxy O-methylsterigmatocystin (HOMST), while the second entails aryl ring cleavage, demethylation, dehydration, decarboxylation, and rearrangement to give aflatoxin - a remarkable sequence of transformations. To test this hypothesis, HOMST has been synthesized by an alkylnitrilium variant of the Houben-Hoesch reaction. The troublesome xanthone carbonyl was protected as a butylene to allow further elaboration of the molecule, and then the product xanthone was restored in a uniquely facile peracid deprotection. Methods were devised to construct the sensitive dihydrobisfuran and to maintain the oxidation state of the partially methylated hydroquinone. Expression of ordA in a yeast membrane preparation enabled the intermediacy of HOMST both to be detected in the conversion of OMST to aflatoxin and to be established directly in the biosynthesis of the mycotoxin. Having secured the role of HOMST in aflatoxin formation, the mechanism of the second oxidative cycle of this P-450 is considered.     

Tautomers of anthrahydroquinones: enzymatic reduction and implications for chrysophanol, monodictyphenone, and related xanthone biosyntheses

Reduction of emodin by sodium dithionite resulted in the formation of two tautomeric forms of emodin hydroquinone. Subsequent conversion by the short-chain dehydrogenase/reductase (SDR) MdpC into the corresponding 3-hydroxy-3,4-dihydroanthracen-1(2H)-one implies that deoxygenation is the first step in monodictyphenone biosynthesis. Implications for chrysophanol formation as well as reaction sequences in the related xanthone, ergochrome, and bianthraquinone biosyntheses are discussed.     

Catalytic Reductive Pinacol‐Type Rearrangement of Unactivated 1,2‐Diols through a Concerted,Stereoinvertive Mechanism

A catalytic pinacol‐type reductive rearrangement reaction of internal 1,2‐diols is reported herein. Several scaffolds not usually amenable to pinacol‐type reactions, such as aliphatic secondary–secondary diols, undergo the transformation well without the need for prefunctionalization. The reaction uses a simple boron catalyst and two silanes and proceeds through a concerted, stereoinvertive mechanism that enables the preparation of highly enantiomerically enriched products. Computational studies have been used to rationalize the preference for migration over direct deoxygenation.     

A Facile Total Synthesis of (±)-Selina-3, 11-Dien-9-Ol

A facile total synthesis of (±)-selina-3, 11-dien-9-ol (1) has been described. The key step is the one-pot reductive deoxygenation of α, β-unsaturated p-tosylhydrazone and reduction of 9-carbonyl of 9 with sodium borohydride.     

New mycotoxins from the scale insect fungus Aschersonia coffeae Henn. BCC 28712

Nine new mycotoxins; five xanthones 1–5, hydroxanthone 6, and three anthraquinones 7–9, together with nine known compounds; sterigmatocystin (10), demethylsterigmatocystin (11), dihydrodemethylsterigmatocystin (12), sterigmatin (13), austocystin F (14), averufin (15), aflatoxin B1, paeciloquinone A, and zeorin, were isolated from the scale insect fungus Aschersonia coffeae Henn. BCC 28712. The structures of these compounds were elucidated using NMR spectroscopic and MS spectrometric analyses. Compounds 1–3 and 6–9 displayed cytotoxic activity while the xanthone 2 and anthraquinones 8 and 9 also showed antimalarial activity.     

Deoxygenation of carbohydrates by thiol-catalysed radical-chain redox rearrangement of the derived benzylidene acetals

Five- or six-membered cyclic benzylidene acetals, derived from 1,2- or 1,3-diol functionality in carbohydrates, undergo an efficient thiol-catalysed radical-chain redox rearrangement resulting in deoxygenation at one of the diol termini and formation of a benzoate ester function at the other. The role of the thiol is to act as a protic polarity-reversal catalyst to promote the overall abstraction of the acetal hydrogen atom by a nucleophilic alkyl radical. The redox rearrangement is carried out in refluxing octane and/or chlorobenzene as solvent at ca. 130 degrees C and is initiated by thermal decomposition of di-tert-butyl peroxide (DTBP) or 2,2-bis(tert-butylperoxy)butane. The silanethiols (Bu(t)O)3SiSH and Pr(i)3SiSH (TIPST) are particularly efficient catalysts and the use of DTBP in conjunction with TIPST is generally the most effective and convenient combination. The reaction has been applied to the mono-deoxygenation of a variety of monosaccharides by way of 1,2-, 3,4- and 4,6-O-benzylidene pyranoses and a 5,6-O-benzylidene furanose. It has also been applied to bring about the dideoxygenation of mannose and of the disaccharide alpha,alpha-trehalose. The use of p-methoxybenzylidene acetals offers no great advantage and ethylene acetals do not undergo significant redox rearrangement under similar conditions. Functional group compatibility is good and tosylate, epoxide and ketone functions do not interfere; it is not necessary to protect free OH groups. Because of the different mechanisms of the ring-opening step (homolytic versus heterolytic), the regioselectivity of the redox rearrangement can differ usefully from that resulting from the Hanessian-Hullar (H.-H.) and Collins reactions for brominative ring opening of benzylidene acetals. When simple deoxygenation of a carbohydrate is desired, the one-pot redox rearrangement offers an advantage over H.-H./Collins-based procedures in that the reductive debromination step (which often involves the use of toxic tin hydrides) required by the latter methodology is avoided.     

Concise Approach to 1,4-Dioxygenated Xanthones via Novel Application of the Moore Rearrangement

The rapid synthesis of 1,4-dioxygenated xanthones and related natural products employing the Moore rearrangement as a key transformation has been developed. The approach features an acetylide stitching step to unite a substituted squaric acid with a protected hydroxy benzaldehyde derivative to provide a key intermediate that undergoes facile Moore rearrangement to deliver a hydroxymethyl aryl quinone. Subsequent oxidation, hydroxy group deprotection and cyclization then affords highly functionalized xanthones. The utility of the approach was demonstrated by its application to a concise and efficient synthesis of the naturally-occurring xanthone 1. The structure of a natural product that had been named dulcisxanthone C was also corrected to that of the xanthone 1.     

Practical and General Alcohol Deoxygenation Protocol

Herein, we describe a practical protocol for the removal of alcohol functional groups through reductive cleavage of their benzoate ester analogs. This transformation requires a strong single electron transfer (SET) reductant and a means to accelerate slow fragmentation following substrate reduction. To accomplish this, we developed a photocatalytic system that generates a potent reductant from formate salts alongside Brønsted or Lewis acids that promote fragmentation of the reduced intermediate. This deoxygenation procedure is effective across structurally and electronically diverse alcohols and enables a variety of difficult net transformations. This protocol requires no precautions to exclude air or moisture and remains efficient on multigram scale. Finally, the system can be adapted to a one-pot benzoylation-deoxygenation sequence to enable direct alcohol deletion. Mechanistic studies validate that the role of acidic additives is to promote the key C(sp³)−O bond fragmentation step.     

Catalytic Reductive Pinacol‐Type Rearrangement of Unactivated 1,2‐Diols through a Concerted,Stereoinvertive Mechanism

A catalytic pinacol‐type reductive rearrangement reaction of internal 1,2‐diols is reported herein. Several scaffolds not usually amenable to pinacol‐type reactions, such as aliphatic secondary–secondary diols, undergo the transformation well without the need for prefunctionalization. The reaction uses a simple boron catalyst and two silanes and proceeds through a concerted, stereoinvertive mechanism that enables the preparation of highly enantiomerically enriched products. Computational studies have been used to rationalize the preference for migration over direct deoxygenation.     

Functional genomic analysis of alkaloid biosynthesis in Hyoscyamus niger reveals a cytochrome P450 involved in littorine rearrangement

Tropane alkaloids are valuable pharmaceutical drugs derived from solanaceous plants such as Hyoscyamus niger (black henbane). The biosynthesis of these molecules, including the nature of the enigmatic rearrangement of (R)-littorine to (S)-hyoscyamine, is not completely understood. To test the hypothesis that a cytochrome P450 enzyme is involved in this rearrangement, we used virus-induced gene silencing to silence a cytochrome P450, CYP80F1, identified from H. niger roots by EST sequencing. Silencing CYP80F1 resulted in reduced hyoscyamine levels and the accumulation of littorine. Hyoscyamine was observed in CYP80F1-expressing tobacco hairy roots supplied with (R)-littorine. Expression in yeast confirmed that CYP80F1 catalyzes the oxidation of (R)-littorine with rearrangement to form hyoscyamine aldehyde, a putative precursor to hyoscyamine, and without rearrangement to form 3'-hydroxylittorine. Our data strongly support the involvement of CYP80F1 in the rearrangement of littorine to hyoscyamine.     

绿色路易斯酸三卤化铟在有机合成中的应用

三卤化铟作为温和的路易斯酸可在水、醇等绿色溶剂中实现高化学选择性、高 区域选择性和高立体选择性的化学转化。综述了三卤化铟在羟醛反应和类羟醛-曼 尼希反应、Fiedel-Crafts反应、环氧化合物的重排反应、α-氨基膦酸的合成、喹 啉环系的构建、酯交换反应、Diels-Alder反应和杂Diels-Alder反应,手性呋喃二 醇的合成、水相中的叠氮解反应和二硫缩醛的制备中的应用,同时还总结了本课题 组将三卤化铟应用于Biginelli反应和还原脱氧反应的反应结果。三卤化铟在有机 合成中潜在的优势将推动“绿色化学”的发展。     

Studies toward the total synthesis of armatol F: stereoselective construction of the C6 and C7 stereocenters and formation of the A-ring skeleton

Armatol F, isolated from the red alga Chondria armata as a polyether triterpene, has a solitary oxepane (A-ring) and a fused tricyclic ether moiety (BCD-ring). The A-ring features a rare cis-relationship between the hydroxy group at the quaternary carbon C6 and the carbon chain at C7. As part of our program toward the total synthesis of armatol F, a new stereoselective method for the construction of the C6 and C7 stereocenters has been developed based on chirality-transferring Ireland-Claisen rearrangement. The A-ring skeleton has also been synthesized from the rearrangement product by a process including ring-closing olefin metathesis.     

Facile one-pot preparation of 2-arylpropionic and arylacetic acids from cyanohydrins by treatment with aqueous HI

A novel one-pot two-step procedure has been developed to synthesize highly substituted 2-arylpropionic and arylacetic acids, by treatment with aqueous HI, from cyanohydrins. The hydrogenolytic reduction of α-hydroxy-2-arylpropionic acids was the key step of the process and the optimization of the reaction conditions led to identify aqueous HI as an appropriate and selective reagent for the reductive deoxygenation of cyanohydrins. The synthetic route described a general and efficient strategy for the preparation of large libraries of phenylacetic and phenylpropionic acids derivatives.     

Total syntheses of the telomerase inhibitors dictyodendrin B, C, and E

Concise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2), C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction to generate an adjacent indole nucleus, and a photochemical 6pi-electrocyclization/aromatization tandem to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal-halogen exchange or cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or -stannanes met with failure.     

Effect of preparation method on the catalytic performance of Ni/H-ZSM-5 for the reductive deoxygenation of cyclohexanone

The effect of the impregnation and co-precipitation-kneading methods on the catalytic performance of the Ni/H-ZSM-5 catalyst was evaluated via catalytic reductive deoxygenation of cyclohexanone in a fixed bed. The catalysts were characterized by X-ray diffraction, nitrogen adsorption, and NH₃-temperature programmed desorption. A sharply acidic and textural change was observed on the catalysts prepared by the different methods, while the metal active phase structure was almost the same. The results of the cyclohexanone reductive deoxygenation reaction indicated that the catalyst based on the co-precipitation-kneading method afforded a higher yield of cyclohexane, and thus proved that the co-precipitation-kneading method is suitable for the preparation of a bi-functional catalyst.     

Theoretical Study of the AlEt3-Promoted Tandem Reductive Rearrangement of Epoxides

The AlEt3-promoted tandem reductive rearrangement reactions of epoxides was studied at B3LYP/6-31G(d,p) level. For the model compound σ-hydroxy epoxides, two possible reaction pathways I and II were calculated. The main difference is the order of ethylene release and six- to five-member ring rearrangement.The ring contraction rearrangement in pathway I is the first step and this step is the rate controlling step with a free energy barrier of 116.62 kJ/mol. For pathway II, the ethylene release occurs first, and is followed by a six-member ring opening reaction which is the rate controlling step, and the barrier is 251.38 kJ/mol.The reason for such high barrier is that the ethylene release results in the following reaction being moredifficult. The results show that pathway I (C-C rearrangement and then ethylene release) is more favorable,which is consistent with experimental results.     

Carrier Protein-Free Enzymatic Biaryl Coupling in Arylomycin A2 Assembly and Structure of the Cytochrome P450 AryC**

The arylomycin antibiotics are potent inhibitors of bacterial type I signal peptidase. These lipohexapeptides contain a biaryl structural motif reminiscent of glycopeptide antibiotics. We herein describe the functional and structural evaluation of AryC, the cytochrome P450 performing biaryl coupling in biosynthetic arylomycin assembly. Unlike its enzymatic counterparts in glycopeptide biosynthesis, AryC converts free substrates without the requirement of any protein interaction partner, likely enabled by a strongly hydrophobic cavity at the surface of AryC pointing to the substrate tunnel. This activity enables chemo-enzymatic assembly of arylomycin A2 that combines the advantages of liquid- and solid-phase peptide synthesis with late-stage enzymatic cross-coupling. The reactivity of AryC is unprecedented in cytochrome P450-mediated biaryl construction in non-ribosomal peptides, in which peptidyl carrier protein (PCP)-tethering so far was shown crucial both in vivo and in vitro.     

Planarisation of Tetracoordinate Carbon Atom. A Further Route ot (all-cis)-[5.5.5.5]Fenestrane

The synthesis of (all-cis)-[5.5.5.5]fenestrane ( 3 ) from dicyclopentadiene is reported. Key step is the Pd-catalyzed reductive deoxygenation of an appropriately substituted cyclooctanone, which leads to transannular C,C-bond formation.     

Synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide by aza-Baylis-Hillman adduct of o-nitrobenzaldehyde

A new and high yielding approach for the synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide is described. The key step consisted in the palladium-catalyzed reductive cyclization of an uncommon 3-ketopyrrole derivative of o-nitrobenzaldehyde, obtained in a straightforward manner through an aza-Baylis-Hillman/ring closing metathesis/aromatization reaction. A deoxygenation reaction of this novel pyrrolo-[3,2-c]quinoline N-oxide afforded a new substituted pyrrolo-[3,2-c]quinoline analogue.