Oxidation of Alcohols in Continuous Flow with a Solid Phase Hypervalent Iodine Catalyst.

One of the most useful transformations in the synthetic chemist arsenal is the oxidation of alcohols to their corresponding carbonyl congeners. Despite its seemingly straightforward nature, this transformative reaction predominantly relies on the use of metals or hazardous reagents, making these processes highly unsustainable. To address this challenge, we have developed a sustainable metal-free method for the oxidation of alcohols in continuous flow. Using a solid phase hypervalent iodine catalyst and nBu4HSO5 as a phase transfer catalyst and co-oxidant, primary and secondary alcohols were selectively oxidized to the corresponding carbonyl motifs. This operationally simple continuous-flow set-up is highly robust (15 cycles run without significant catalyst leaching or loss of reaction efficiency), uses green solvents, such as acetonitrile or acetic acid, and is readily scalable.

Total synthesis of both enantiomers of the biosurfactant aureosurfactin via bidirectional synthesis with a chiral Horner-Wittig building block.

Aureosurfactin is a novel biosurfactant that exhibits similar surface tension activity to known biosurfactants. In this work, we now report a facile synthesis for aureosurfactin using a bidirectional synthetic strategy. Both enantiomers of the target compound were accessed from the (S)-building block, derived from the same chiral pool starting material.

Total Synthesis of Cryptoconcatone D via Construction of 1,3-Diol Units Using Chiral Horner-Wittig Reagents.

The modular synthesis of 1,3-polyols using a chiral phosphine oxide building block is reported. This versatile building block works in a repetitive way for the stereocontrolled synthesis of a tetraol key intermediate, which serves for the first total synthesis of the potentially anti-inflammatory natural product cryptoconcatone D. A new route toward the chiral building block is also presented: Starting from 2-deoxy-d-ribose, the optimized sequence now makes the use of the building block more attractive to practicing chemists again.

Inhibition of cytochrome P450 monooxygenase-catalyzed oxylipin formation by flavonoids: Evaluation of structure-activity relationship towards CYP4F2-selective inhibitors.

Epoxy- and hydroxy-fatty acids are physiologically active lipid mediators which are formed from arachidonic acid and other fatty acids by cytochrome P450 monooxygenase (CYP) catalytic activity. In this study, we investigated the structure-activity relationship of the inhibition of fatty acid-oxidizing CYP by flavonoids. A sum of 65 naturally occurring as well as new flavonoids were synthesized and tested in a multi-enzyme assay. Substituents at C2' and C7-position of the flavone structure caused epoxygenase blockade, while electronegative substituents at C4'-position led to ω-hydroxylase-selective inhibition. We identified 4'-trifluoromethylflavone as a potent and selective compound, inhibiting 20-HETE formation with an IC50 of 2.8 µM (1.3 µM-6.1 µM) in human liver microsomes. This inhibition is achieved by selective inhibition of CYP4F2 [IC50: 0.76 µM (0.42 µM-1.4 µM)], while the other human ω-hydroxylating CYP, CYP4A11, is not affected. The compound is also active in microsomes from rat and mouse liver [IC50: 1.4 µM (0.77 µM-2.7 µM) and 0.71 µM (0.24 µM-2.2 µM), respectively]. Moreover, it exhibits moderate permeability properties in PAMPA and CaCo-2 transwell systems (papp: 4.6 ±â€¯0.6 × 10-6 cm/s and 4.1 ±â€¯0.4 × 10-6 cm/s, respectively) and is stable to metabolic conversion in vitro. With this inhibitor, we provide a novel tool to selectively investigate the CYP4F2-catalyzed 20-HETE formation and its role in physiology.

Ring Expansion of 2-Azido-2-phenyl-indan-1,3-dione for the Generation of Heterocyclic Scaffolds.

A novel ring expansion based on the readily available 2-azido-2-phenyl-indan-1,3-dione is described. Treatment with primary amines and cesium carbonate in a two-step sequence gives rise to 3-amino-2,3-dihydroisoquinoline-1,4-diones with an unprecedented substitution pattern. The corresponding conversion using amino acid methyl esters leads directly to a novel tricyclic 1,10a-dihydroimidazo-isoquinoline-2,5,10-trione scaffold, a structure that has never been reported before, to the best of our knowledge.

Human lipoxygenase isoforms form complex patterns of double and triple oxygenated compounds from eicosapentaenoic acid.

Lipoxygenases (ALOX) are lipid peroxidizing enzymes that catalyze the biosynthesis of pro- and anti-inflammatory lipid mediators and have been implicated in (patho-)physiological processes. In humans, six functional ALOX isoforms exist and their arachidonic acid oxygenation products have been characterized. Products include leukotrienes and lipoxins which are involved in the regulation of inflammation and resolution. Oxygenation of n3-polyunsaturated fatty acids gives rise to specialized pro-resolving mediators, e.g. resolvins. However, the catalytic activity of different ALOX isoforms can lead to a multitude of potentially bioactive products. Here, we characterized the patterns of oxygenation products formed by human recombinant ALOX5, ALOX15, ALOX15B and ALOX12 from eicosapentaenoic acid (EPA) and its 18-hydroxy derivative 18-HEPE with particular emphasis on double and triple oxygenation products. ALOX15 and ALOX5 formed a complex mixture of various double oxygenation products from EPA, which include 5,15-diHEPE and various 8,15-diHEPE isomers. Their biosynthetic mechanisms were explored using heavy oxygen isotopes (H218O, 18O2 gas) and three catalytic activities contributed to product formation: i) fatty acid oxygenase activity, ii) leukotriene synthase activity, iii) lipohydroperoxidase activity. For ALOX15B and ALOX12 more specific product patterns were identified, which was also the case when these enzymes reacted in concert with ALOX5. Several double oxygenated compounds were formed from 18-HEPE by ALOX5, ALOX15B and ALOX12 including previously identified resolvins (RvE2, RvE3), while formation of triple oxygenation products, e.g. 5,17,18-triHEPE, required ALOX5. Taken together our data show that EPA can be converted by human ALOX isoforms to a large number of secondary oxygenation products, which might exhibit bioactivity.

Activation of a Metal-Halogen Bond by Halogen Bonding.

In recent years, the non-covalent interaction of halogen bonding (XB) has found increasing application in organocatalysis. However, reports of the activation of metal-ligand bonds by XB have so far been limited to a few reactions with elemental iodine or bromine. Herein, we present the activation of metal-halogen bonds by two classes of inert halogen bond donors and the use of the resulting activated complexes in homogenous gold catalysis. The only recently explored class of iodolium derivatives were shown to be effective activators in two test reactions and their activity could be modulated by blocking of the Lewis acidic sites. Bis(benzimidazolium)-based halogen bonding activators provided even more rapid conversion, while the non-iodinated reference compound showed little activity. The role of halogen bonding in the activation of metal-halogen bonds was further investigated by NMR experiments and DFT calculations, which support the mode of activation occurring via halogen bonding.

Rubazonic Acids and Their Synthesis.

Rubazonic acids are a class of dyes that are long-known, but studies on their syntheses and uses are rare. We now describe an experimentally simple and highly practical one-pot procedure for their synthesis starting from easily accessible 1H-pyrazol-5(4H)-ones. This protocol provides direct access to a broad range of the desired rubazonic acid derivatives through oxidative diazidation combined with a reductive work-up, without the need to isolate the potentially hazardous diazido compounds generated en route the target compounds. We also show how more challenging variants of rubazonic acid are efficiently prepared using an alternative two-step procedure and controlled hydrogenation conditions.

A Synthetic Route Toward Tetrazoles: The Thermolysis of Geminal Diazides.

A new synthetic route toward the tetrazole core is described, which is based on a general fragmentation pattern that was found in a range of compounds featuring geminal diazido units. Through a simple two-step procedure, the synthesis of structurally diverse target compounds containing a tetrazole, such as tetrazoloquinoxalinones, benzoylaryltetrazoles, tetrazolotriazinones, and tetrazoloazepinones, was easily accomplished, starting from broadly accessible substrates (i.e., oxindoles, diarylethanones, pyrazolones, and phenanthrols). The initial oxidative diazidation reaction with iodine and sodium azide under mild conditions is followed by the thermal fragmentation under microwave irradiation, leading to the tetrazole products. Noteworthy, an experimental solution is presented in which the potentially hazardous diazide intermediates are not isolated and the concentration of crude reaction mixtures containing diazides is not required to achieve the tetrazoles in good yields.

The Deazidoalkoxylation: Sequential Nucleophilic Substitutions with Diazidated Diethyl Malonate.

Diazidated malonamides derived from amines and diazidated diethyl malonate react with lithiated alcohols through nucleophilic substitution reactions where azide acts as an unconventional leaving group. This deazidoalkoxylation leads to the formal construction of N, O-acetals, and the remaining azide functionality is a useful entry point for further functionalizations through, for example, standard cycloaddition chemistry. Thus, the presented chemistry provides an easy route toward densely functionalized molecules: Amines, alcohols, and alkynes can be attached onto the small malonate core unit in a sequential manner.

Synthesis and Reactivity of 3,3-Diazidooxindoles.

The synthesis of previously unknown 3,3-diazidooxindoles as synthetically useful derivatives of isatins was accomplished through the direct oxidative diazidation of 2-oxindoles. The method yielded the diazido compounds from the starting oxindoles under mild and simple conditions with NaN3 and iodine, in good yields. The notable reactivity of this new class of compounds toward primary and secondary nucleophilic amines is also described, which gives access to either 4-imino-3,4-dihydroquinazolin-2(1 H)-one derivatives or cyanophenylureas.

Pathways in the Degradation of Geminal Diazides.

The degradation of geminal diazides is described. We show that diazido acetates are converted into tetrazoles through the treatment with bases. The reaction of dichloro ketones with azide anions provides acyl azides, through in situ formation of diazido ketones. We present experimental and theoretical evidence that both fragmentations may involve the generation of acyl cyanide intermediates. The controlled degradation of terminal alkynes into amides (by loss of one carbon) or ureas (by loss of two carbons) is also shown.

Cleavage of 1,3-dicarbonyls through oxidative amidation.

A mild and convenient protocol for the oxidative cleavage of 1,3-diketone compounds is described. Under metal-free conditions, the method converts the 1,3-dicarbonyls into amides when treated with (nBu4N)N3 and iodine in the presence of an amine at room temperature. Using this method, a range of 1,3-dicarbonyls with various structural motifs including sterically demanding substituents and ordinary functional groups were easily fragmented, and it is demonstrated that cyclic 1,3-dicarbonyls can be directly transformed into acyclic diamides through ring-opening. Initial mechanistic studies show that diazidation of the enol form is followed by nucleophilic substitution with the amine.

The asymmetric reduction of imidazolinones with trichlorosilane.

It is shown how imidazolinones are reduced by trichlorosilane in a highly enantioselective fashion when treated with a novel Lewis base organocatalyst that is based on a 2,2'-bispyrrolidine core. Under mild reaction conditions and with low catalyst loading the hydrosilylation reaction provides a broad range of chiral imidazolidinones with various structural motifs including sterically demanding substituents, alkyls and aryls.

Enhanced site-selectivity in acylation reactions with substrate-optimized catalysts on solid supports.

A concept for site selective acylation of poly-hydroxylated substrates is presented where polymer-supported catalysts are employed: catalytically active DMAP units were combined with a library of small molecule peptides attached to the solid phase with the goal to identify substrate-optimized catalysts through library screening. For selected examples, we demonstrate how the optimized catalysts can convert "their" substrate with a markedly enhanced site-selectivity, compared to only DMAP. Due to the solid support, product purification is significantly simplified, and the peptidic catalysts can be easily reused in multiple cycles while conserving its efficiency.

Thermolysis of Geminal Diazides: Reagent-Free Synthesis of 3-Hydroxypyridines.

An operationally simple protocol for the rapid and efficient construction of highly substituted 3-hydroxypyridines is presented. The thermally induced cyclization of easily constructed geminal diazides derived from ß-ketoesters having an additional olefin moiety affords the title compounds in yields up to 97% under reagent-free conditions. The new method allows for the synthesis of preparative quantities of material. Additionally, the synthetic utility of the pyridine products for the synthesis of valuable heterocycles is described.

Site-Selective Acylations with Tailor-Made Catalysts.

The acylation of alcohols catalyzed by N,N-dimethylamino pyridine (DMAP) is, despite its widespread use, sometimes confronted with substrate-specific problems: For example, target compounds with multiple hydroxy groups may show insufficient selectivity for one hydroxyl, and the resulting product mixtures are hardly separable. Here we describe a concept that aims at tailor-made catalysts for the site-specific acylation. To this end, we introduce a catalyst library where each entry is constructed by connecting a variable and readily tuned peptide scaffold with a catalytically active unit based on DMAP. For selected examples, we demonstrate how library screening leads to the identification of optimized catalysts, and the substrates of interest can be converted with a markedly enhanced site-selectivity compared with only DMAP. Furthermore, substrate-optimized catalysts of this type can be used to selectively convert "their" substrate in the presence of structurally similar compounds, an important requisite for reactions with mixtures of substances.

Versatile process for the stereodiverse construction of 1,3-polyols: iterative chain elongation with chiral building blocks.

A versatile process for the construction of 1,3-polyols, a key structural element of polyketide-type natural products, is presented. The modular synthesis strategy involves the iterative chain elongation with novel four-carbon building blocks to access all possible stereoisomers of a growing 1,3-polyol chain. These chiral building blocks are designed to install four carbon atoms with two stereogenic centres by performing only four experimentally simple steps per elongation cycle, thus making these building blocks attractive for the realization of a universal platform from which to access a diverse range of polyketidic molecules.

Synthesis of geminal bis- and tristriazoles: exploration of unconventional azide chemistry.

A range of geminal bis- and tristriazoles are presented. These rare and hardly studied compound classes were easily synthesized using ethyl 2,2-diazido-3-oxobutanoate as the common starting point. Firstly, CuAAC-reaction with an alkyne afforded the corresponding deacetylated bistriazoles. Upon further azidation yielding azidomethylenebistriazoles, a second CuAAC-functionalization then led to the creation of the geminal tristriazole compounds.

Geminal Diazides Derived from 1,3-Dicarbonyls: A Protocol for Synthesis.

Geminal diazides constitute a rare class of compounds where only a limited number of methods are available for their synthesis. We present the reaction of 1,3-dicarbonyl compounds (as exemplified by malonates, 3-oxoesters, and 1,3-diketones) with molecular iodine and sodium azide in aqueous DMSO providing a general access to geminal diazides. A broad range of geminal diazides with various structural motifs including sterically demanding substituents and ordinary functional groups were synthesized, and it was shown that the diazidation of 1,3-dicarbonyls can be selectively achieved even in the presence of other 1,3-dicarbonyls with substituents at 2-position. Additionally, several diazides were studied regarding their thermal stability.