Organic & Biomolecular Chemistry (v.14, #37)
Front cover (8625-8626).
Contents list (8627-8635).
Chemoselective photooxygenations of furans bearing unprotected amines: their use in alkaloid synthesis by T. Montagnon; D. Kalaitzakis; M. Sofiadis; G. Vassilikogiannakis (8636-8640).
Very recent investigations are described, which have shown how basic and unprotected nitrogen functionalities can be included, problem-free, in the furan photooxidation step of singlet oxygen-initiated cascade reaction sequences. The amine groups do not react with singlet oxygen, but, instead, participate later on in the sequences that ultimately yield a diverse range of important alkaloid motifs. To illustrate the versatility of this chemistry, six natural products were synthesised very rapidly and efficiently. Furthermore, all the new technologies operated under green conditions and without the use of a single protecting group.
The past, present, and future of the Yang reaction by Chuo Chen (8641-8647).
Photoexcited ketones have diradical characteristics and are functionally similar to high-spin metal–oxo species that are frequently used to catalyze C–H oxidation. First discovered by Yang in 1958, photoexcited ketones can abstract a hydrogen atom from hydrocarbons inter- or intramolecularly. Coupling with atom-transfer, group-transfer, or radical addition, the Yang reaction can be used to achieve various types of C–H functionalization. We provide in this article an overview of triplet ketone-mediated or catalyzed C–H functionalization reactions.
Using carbohydrate-based biomaterials as scaffolds to control human stem cell fate by Jing Hu; Peter H. Seeberger; Jian Yin (8648-8658).
Given the important roles of carbohydrates in numerous signalling pathways, cell–cell interactions and cell–matrix interactions, a variety of scaffolds based on natural polysaccharides and glycoproteins that are mostly found in the native extracellular matrix (ECM) have been established and investigated as stem cell culture systems. Stem cells have been extensively used in cell therapy and tissue engineering, and the ability to create a suitable environment to direct stem cell behavior is critical for such endeavors. It is a great challenge to construct scaffolds that mimic the native “niche” of stem cells. The present review describes the current statuses and applications of several natural polysaccharide and glycoprotein scaffolds for use in tissue engineering. In the future, carbohydrate-based biomaterials may be used to create powerful scaffolds that can regulate the stem cell fate.
Solid-phase synthesis and fluorine-18 radiolabeling of cycloRGDyK by Ryan A. Davis; Kevin Lau; Sven H. Hausner; Julie L. Sutcliffe (8659-8663).
Solid-phase peptide synthesis, head-to-tail cyclization, and subsequent radiolabeling provided a reproducible, simple, rapid synthetic method to generate the cyclic peptide radiotracer cRGDyK([18F]FBA). Herein is reported the first on-resin cyclization and 18F-radiolabeling of a cyclic peptide (cRGDyK) in an overall peptide synthesis yield of 88% (cRGDyK(NH2)) and subsequent radiolabeling yield of 14 ± 2% (decay corrected, n = 4). This approach is generally applicable to the development of an automated process for the synthesis of cyclic radiolabeled peptides for positron emission tomography (PET).
FT-IR and NMR structural markers for thiazole-based γ-peptide foldamers by C. Bonnel; B. Legrand; J.-L. Bantignies; H. Petitjean; J. Martinez; N. Masurier; L. T. Maillard (8664-8669).
Nuclear magnetic resonance (NMR) spectroscopy has been established as a potent method for the determination of foldamer structures in solution. However, the NMR techniques could be limited by averaging, so additional experimental techniques are often needed to fully endorse the folding properties of a sequence. We have recently demonstrated that oligo-γ-peptides composed of 4-amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) adopt an original helical fold stabilized by hydrogen bonds forming C9 pseudocycles. The main objective of the present work is to reinvestigate the folding of ATC oligomer 1 in order to identify reliable FT-IR and NMR structural markers that are of value for tracking the degree of organization of ATC-based peptides.
Bicyclic isoureas derived from 1-deoxynojirimycin are potent inhibitors of β-glucocerebrosidase by Alen Sevšek; Maša Čelan; Bibi Erjavec; Linda Quarles van Ufford; Javier Sastre Toraño; Ed E. Moret; Roland J. Pieters; Nathaniel I. Martin (8670-8673).
A series of bicyclic isourea derivatives were prepared from 1-deoxynojirimycin using a concise synthetic protocol proceeding via a guanidino intermediate. Inhibition assays with a panel of glycosidases revealed that these deoxynojirimycin-derived bicyclic isoureas display very potent inhibition against human recombinant β-glucocerebrosidase with IC50 values in the low nanomolar range.
Reactions of 1,2-diaza-1,3-butadienes with propargyl alcohol as an approach to novel bi-heterocyclic systems by L. De Crescentini; F. R. Perrulli; G. Favi; S. Santeusanio; G. Giorgi; O. A. Attanasi; F. Mantellini (8674-8678).
Here we describe the reaction of 1,2-diaza-1,3-dienes and propargyl alcohol furnishing α-(prop-2-yn-1-yloxy)hydrazones that are converted into novel alkyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-dien-6-ones, by means of 2,3-Wittig rearrangement under very mild conditions. The same α-(prop-2-yn-1-yloxy)hydrazones, treated with benzyl azides furnish the corresponding α-[(1,2,3-triazol-4-yl)methoxy]hydrazones, via Cu(ii)-catalyzed 1,3-dipolar cycloaddition. Their subsequent base-promoted cyclization produces interesting pyrazolone–triazole derivatives. The impact of this work can be ascribable to the attractiveness of the bi-heterocyclic systems obtained and to the ease of the synthetic methodologies proposed.
A ThDP-dependent enzymatic carboligation reaction involved in Neocarazostatin A tricyclic carbazole formation by Li Su; Meinan Lv; Kwaku Kyeremeh; Zixin Deng; Hai Deng; Yi Yu (8679-8684).
Although the biosynthetic pathway of Neocarazostatin A (1) has been identified, the detailed enzymatic reactions underlying the assembly of the carbazole ring still remain largely unknown. We demonstrate here that NzsH, a putative thiamine diphosphate dependent enzyme, can catalyze an acyloin coupling reaction between indole-3-pyruvate and pyruvate to generate a β-ketoacid intermediate. Our findings thus shed light on further characterization of the unusual biosynthetic pathway of the bacterial tricyclic carbazole alkaloids.
Chemoselective acylation of benzimidazoles with phenylacetic acids under different Cu catalysts to give fused five-membered N-heterocycles or tertiary amides by Shaoyu Mai; Yingwei Zhao; Qiuling Song (8685-8690).
C–N bond formation via a copper-catalyzed aerobic oxidative decarboxylative tandem protocol was realized. The phenylacetic acids which contain ortho-X (X = F or Br) on the aromatic ring will render a fused five-membered heterocycle via a tandem aromatic nucleophilic substitution and aerobic oxidative decarboxylative acylation at the C(sp2)–H bond of benzimidazoles under the Cu(OAc)2/K2CO3/BF3·Et2O catalytic system, while with CuBr as the catalyst and pyridine as the base, N-acylation occurred and tertiary amides were obtained.
Design, synthesis and biological activities of new brassinosteroid analogues with a phenyl group in the side chain by M. Kvasnica; J. Oklestkova; V. Bazgier; L. Rárová; P. Korinkova; J. Mikulík; M. Budesinsky; T. Béres; K. Berka; Q. Lu; E. Russinova; M. Strnad (8691-8701).
We have prepared and studied a series of new brassinosteroid derivatives with a p-substituted phenyl group in the side chain. To obtain the best comparison between molecular docking and biological activities both types of brassinosteroids were synthesized; 6-ketones, 10 examples, and B-lactones, 8 examples. The phenyl group was introduced into the steroid skeleton by Horner–Wadsworth–Emmons. The docking studies were carried out using AutoDock Vina 1.05. Plant biological activities were established using different brassinosteroid bioassays in comparison with natural brassinosteroids. Differences in the production of the plant hormone ethylene were also observed in etiolated pea seedlings after treatment with new brassinosteroids. The most active compounds were lactone 8f and 6-oxo derivatives 8c and 9c, their biological activities were comparable or even better than naturally occurring brassinolide. Finally the cytotoxicity of the new derivatives was studied using human normal and cancer cell lines.
Pd-Catalyzed C(sp3)–C(sp2) cross-coupling of Y(CH2SiMe3)3(THF)2 with vinyl bromides and triflates by Guilong Cai; Zhibing Zhou; Wenchao Wu; Bo Yao; Shaowen Zhang; Xiaofang Li (8702-8706).
Pd-Catalyzed C(sp3)–C(sp2) cross-coupling of Y(CH2SiMe3)3(THF)2 with vinyl bromides and triflates has been developed for efficient synthesis of various allyltrimethylsilanes. The cross-coupling reaction was conducted at room temperature with low catalyst loading of either Pd(PPh3)4 or Pd(PPh3)2Cl2, and exhibited high efficiency and a broad substrate scope. In combination with the cross-coupling by the Lewis-acid catalyzed Hosomi–Sakurai reaction, a novel three-component one-pot cascade reaction was then accomplished to deliver homoallylic alcohols and ethers with high regioselectivity and diastereoselectivity. The three-component reaction defined the yttrium complex as a novel one-carbon synthon, which could either trigger bifunctionalization of alkenes or link two electrophiles and would find applications in organic synthesis.
Tetra-porphyrin molecular tweezers: two binding sites linked via a polycyclic scaffold and rotating phenyl diimide core by R. B. Murphy; R. E. Norman; J. M. White; M. V. Perkins; M. R. Johnston (8707-8720).
The synthesis of a tetra-porphyrin molecular tweezer with two binding sites is described. The bis-porphyrin binding sites are aligned by a polycyclic scaffold and linked via a freely rotating phenyl diimide core. Synthesis was achieved using a divergent approach employing a novel coupling method for linking two polycyclic units to construct the core, with a copper(ii)-mediated phenyl boronic acid coupling found to extend to our polycyclic imide derivative. We expect this chemistry to be a powerful tool in accessing functional polycyclic supramolecular architectures in applications where north/south reactivity and/or directional interactions between modules are important. Porphyrin receptor functionalisation was undertaken last, by a four-fold ACE coupling reaction on the tetra-epoxide derivative of the core.
Synthesis of pyrazolo[1,5-a]quinoxalin-4(5H)-ones via one-pot amidation/N-arylation reactions under transition metal-free conditions by Carson Wiethan; Steffany Z. Franceschini; Helio G. Bonacorso; Mark Stradiotto (8721-8727).
An efficient one-pot transition metal-free procedure for the synthesis of new pyrazolo[1,5-a]quinoxalin-4(5H)-ones from easily prepared 1-(2-chlorophenyl-5-ethylcarboxylate)pyrazoles and various primary alkylamines is described. The key steps involved in the synthesis of the new 5,6-fused ring system are the formation of an amide intermediate followed by an intramolecular N-arylation reaction via nucleophilic aromatic substitution.
A protecting group-free synthesis of (−)-hortonones A–C from the Inhoffen–Lythgoe diol by Hovsep Stambulyan; Thomas G. Minehan (8728-8731).
A synthesis of hortonones A–C has been accomplished from vitamin D2via the Inhoffen–Lythgoe diol without the use of protective groups. Key steps in the syntheses include a TMS-diazomethane mediated regioselective homologation of the cyclohexanone ring to a cycloheptanone moiety and a sodium naphthalenide-mediated allylic alcohol transposition. It has been found that the absolute configuration of the natural hortonones is opposite that of the synthetic material prepared from vitamin D2.
A facile hybrid ‘flow and batch’ access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones by Andrew J. S. Lin; Cecilia C. Russell; Jennifer R. Baker; Shelby L. Frailey; Jennette A. Sakoff; Adam McCluskey (8732-8742).
We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylates (12a–l) and N-ethyl-3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamides (13a–l) in 38–87% yields. This scaffold is poorly described in the chemical literature. Screening against a panel of 11 cancer and one normal cell line showed that the amide linked library 13a–l was devoid of toxicity. Whereas the ester linked analogues 12b, 12c, 12g, 12j and 12l were highly cytotoxic with growth inhibition (GI50) values from 0.34 to >50 μM across all cell lines, with the 2-OH-Ph substituted 12l analogue presenting with sub-micromolar potency against the A2780 (ovarian; 0.34 ± 0.04 μM), BEC-2 (glioblastoma; 0.35 ± 0.06 μM), MIA (pancreas; 0.91 ± 0.054 μM) and SMA (murine glioblastoma; 0.77 ± 0.029 μM) carcinoma cell lines. Interestingly, the U87 glioblastoma cell line showed inherent resistance to growth inhibition by all analogues (GI50 32 to >50 μM) while the A2780 cells were highly sensitive (GI50 3.8–0.34 μM), suggesting that the analogues developed herein may be valuable lead compounds for the development of ovarian carcinoma specific cytotoxic agents. The differences in amide versus ester cytotoxicity was consitent with esterase cleaveage to release the cytotoxic warhead.
Bifunctional aryloxyphosphoramidate prodrugs of 2′-C-Me-uridine: synthesis and anti-HCV activity by Munmun Maiti; Ling-Jie Gao; Chunsheng Huang; Roger G. Ptak; Michael G. Murray; Steven De Jonghe; Piet Herdewijn (8743-8757).
In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity of 2′-C-Me-uridine, we have synthesized for the first time a series of l-glutamic acid, l-serine, l-threonine and l-tyrosine containing aryloxyphosphoramidate prodrugs of 2′-C-Me-uridine. Evaluation of their activity against HCV revealed that they displayed very potent anti-HCV activity, with EC50 values that are in the same range as of Sofosbuvir.
Asymmetric total synthesis of (+)-O-methylasparvenone, a rare nitrogen-free serotonin 2C receptor antagonist by Raphaël Lafleur-Lambert; John Boukouvalas (8758-8763).
The first enantioselective synthesis of the fungal metabolite (+)-O-methylasparvenone was achieved in eight steps and 22% overall yield from inexpensive 3,4,5-trimethoxybenzaldehyde dimethyl acetal. Key steps include (i) early-stage asymmetric alkynylation of an aromatic aldehyde with a propiolate, (ii) intramolecular Friedel–Crafts acylation, and (iii) site-selective cleavage of an aryl methyl ether.
Racemic and enantioselective metal-catalyzed synthesis of SF5-containing diarylmethanols by Justine Desroches; Ariane Tremblay; Jean-François Paquin (8764-8780).
The racemic and enantioselective metal-catalyzed addition of arylboronic acids to 4- and 3-(pentafluorosulfur)benzaldehydes is reported. The racemic synthesis was accomplished using a Pd-based system and a wide range of arylboronic acids could be used, resulting in yields of 42 to 98% of the corresponding SF5-containing diarylmethanols. A ruthenium-based system, along with (R,R)-Me-BIPAM as the chiral ligand, was investigated and optimized for the enantioselective version. In this case, while the chiral SF5-containing diarylmethanols were generally obtained in good yields (up to 94%) and enantioselectivities (up to 98% ee), limitations were also observed. For instance, 4-(pentafluorosulfur)benzaldehyde generally provided slightly better yields than 3-(pentafluorosulfur)benzaldehyde. In addition, lower yields and enantioselectivities were observed when using either 4- and 3-substituted arylboronic acids bearing electron-withdrawing (e.g., CO2Et, NO2, CF3) or 2-substituted arylboronic acids (regardless of the nature of the substituent). Overall, the SF5-containing diarylmethanols described herein represent novel and potentially useful fluorinated building blocks for the synthesis of biologically active compounds.
Double heteroannulation of S,N-acetals: a facile access to quinolone derivatives by Manojkumar Janni; Sahil Arora; S. Peruncheralathan (8781-8788).
A rapid construction of quinolone fused heterocycles from single S,N-acetal precursors via double heteroannulation is described. The base, radical and metal-mediated reactions can control the C–N, C–S and C–O bond formations of the S,N-acetal with high chemoselectivity.
Total synthesis of cananginone C and structural revision of debilisone A by Tapan Kumar Kuilya; Rajib Kumar Goswami (8789-8799).
A short, convergent and general strategy for stereoselective total synthesis of biologically active α-substituted γ-hydroxymethyl γ-lactone based natural products cananginone C and debilisone A has been developed. The salient features of this synthesis include Cadiot–Chodkiewicz coupling, Evans allylation, Sharpless asymmetric dihydroxylation and γ-lactonization. The originally proposed structure of debilisone A has been revised.
Introduction of a tailor made anion receptor into the side chain of small peptides allows fine-tuning the thermodynamic signature of peptide–DNA binding by Mao Li; Stefanie Schlesiger; Shirley K. Knauer; Carsten Schmuck (8800-8803).
The binding between peptides and DNA is often driven by entropic forces. We demonstrate herein a new approach to shift the thermodynamic profile of peptide/DNA binding from entropy to enthalpy driven. This eventually leads to higher compacted DNA aggregates which are important for gene transfection.
Chemical synthesis and enzymatic properties of RNase A analogues designed to enhance second-step catalytic activity by David J. Boerema; Valentina A. Tereshko; Junliang Zhang; Stephen B. H. Kent (8804-8814).
In this paper, we have used total chemical synthesis of RNase A analogues in order to probe the molecular basis of enzyme catalysis. Our goal was to obligately fill the adenine-binding pocket on the enzyme molecule, and to thus pre-orient the imidazole side chain of His119 in its catalytically productive orientation. Two designed analogues of the RNase A protein molecule that contained an adenine moiety covalently bound to distinct amino acid side chains adjacent to the adenine binding pocket were prepared. A crystal structure of one analogue was determined at 2.3 Å resolution. Kinetic data for RNA transphosporylation and 2′,3′ cyclic mononucleotide hydrolysis were acquired for the adenine-containing RNase A analogue proteins. As anticipated, the presence of a covalently attached adenine on the enzyme molecule decreased the rate of transphosphorylation and increased the rate of hydrolysis, although the magnitude of the effects was small. This work illustrates the use of total protein synthesis to investigate the chemistry of enzyme catalysis in ways not possible through traditional biochemistry or molecular biology.
A direct assay of butyrylcholinesterase activity using a fluorescent substrate by Seungyoon Kang; Suji Lee; Woojin Yang; Jiwon Seo; Min Su Han (8815-8820).
In this study, we report a direct fluorometric assay for butyrylcholinesterase (BChE) activity and screening of its inhibitor, using a fluorescent substrate. 2-(2-(5,6-Dimethoxy-1,3-dioxoisoindolin-2-yl)acetoxy)-N,N,N-trimethylethan-1-ammonium iodide (1) was hydrolyzed by BChE, and its fluorescence was quenched by an intramolecular photoinduced electron transfer process. The resulting change in fluorescence provided a facile method for real-time BChE activity testing. Remarkably, 1 was selectively hydrolyzed by BChE, even in the presence of excess acetylcholinesterase, thereby facilitating the specific monitoring of BChE activity. This assay method is also useful for screening potential BChE inhibitors. Given its simplicity, selectivity, and higher assay speed, this method may be extended to high-throughput screening of BChE inhibitors and relevant drug discovery.
Total synthesis of mangiferin, homomangiferin, and neomangiferin by Xiong Wei; Danlin Liang; Qing Wang; Xiangbao Meng; Zhongjun Li (8821-8831).
Total synthesis of mangiferin, homomangiferin, and neomangiferin, three C-glycosyl xanthone natural products with a wide spectrum of pharmacological effects, has been achieved starting from 2,3,4,6-tetra-O-benzyl-α/β-d-glucopyranose. The key steps involve a stereoselective Lewis acid promoted C-glycosylation of protected phloroglucinol with tetrabenzylglucopyranosyl acetate and a highly regioselective base-induced cyclization for the construction of the core xanthone skeleton.
Substitution dependent stereoselective construction of bicyclic lactones and its application to the total synthesis of pyranopyran, tetraketide and polyrhacitide A by B. V. Subba Reddy; Dhanraj O. Biradar; Y. Vikram Reddy; J. S. Yadav; Kiran Kumar Singarapu; B. Sridhar (8832-8837).
A novel bicyclization strategy has been developed for the stereoselective synthesis of bicyclic lactones, i.e. 7-aryl or alkyl-2,6-dioxabicyclo[3.3.1]nonan-3-ones through a domino cyclization of (R)-3-hydroxyhex-5-enoic acid with an aldehyde in the presence of 10 mol% trimethylsilyltriflate under mild conditions. The salient features of this methodology are high yields, excellent selectivity, low catalyst loading and faster reaction times. This method has been successfully applied to the total synthesis of pyranopyran, tetraketide and polyrhacitide A.
4,4′-Bismoschamine: biomimetic synthesis and evidence to support structural equivalency to montamine by Kaitlin G. Henry; Lachlan M. Blair; Jonathan Sperry; Elizabeth A. Colby Davie (8838-8847).
The dimeric natural product montamine was originally reported as two N-feruloylserotonin (moschamine) units linked by a nitrogen–nitrogen bond, but our recent synthesis of this symmetrical diacyl hydrazide structure revealed this to be incorrect. We subsequently hypothesized that the moschamine subunits were linked through the indole C4 site and that montamine was structurally identical to 4,4′-bismoschamine, a known natural product present in safflower oil. However, given that authentic samples of both montamine and 4,4′-bismoschamine were unavailable and that the NMR data for the natural products were recorded in different solvents, we were unable to unequivocally prove this hypothesis. A recent publication that claims montamine and 4,4′-bismoschamine are not the same natural product prompts us to disclose our own findings on this matter. A biomimetic synthesis of 4,4′-bismoschamine was developed that hinged on oxidative coupling of N-Boc-serotonin followed by elaboration of the resulting 4,4′-dimer to the natural product. A detailed comparison of the NMR data for synthetic 4,4′-bismoschamine with that reported for montamine revealed that while the 1H NMR data were in good agreement, the 13C NMR data displayed some discrepancies. In light of this result, the NMR data for several literature compounds was analyzed, the results of which revealed that the upfield chemical shifts of the methylene protons in the 1H NMR of montamine is unique to 4,4′-bistryptamines, supporting our initial statement that montamine and 4,4′-bismoschamine are structurally equivalent. Given that the main differences in the 13C NMR data between montamine and synthetic 4,4′-bismoschamine occur at the quaternary carbons, we propose that these peaks have been misassigned from a 13C NMR spectrum that was obtained from an impure sample and/or the small amount of montamine (4 mg) isolated from the natural source.
Ethionamide biomimetic activation and an unprecedented mechanism for its conversion into active and non-active metabolites by Julie Laborde; Céline Deraeve; Carine Duhayon; Geneviève Pratviel; Vania Bernardes-Génisson (8848-8858).
Ethionamide (ETH), a second-line anti-tubercular drug that is regaining a lot of interest due to the increasing cases of drug-resistant tuberculosis, is a pro-drug that requires an enzymatic activation step to become active and to exert its therapeutic effect. The enzyme responsible for ETH bioactivation in Mycobacterium tuberculosis is a monooxygenase (EthA) that uses flavin adenine dinucleotide (FAD) as a cofactor and is NADPH- and O2-dependant to exert its catalytic activity. In this work, we investigated the activation of ETH by various oxygen-donor oxidants and the first biomimetic ETH activation methods were developed (KHSO5, H2O2, and m-CPBA). These simple oxidative systems, in the presence of ETH and NAD+, allowed the production of short-lived radical species and the first non-enzymatic formation of active and non-active ETH metabolites. The intermediates and the final compounds of the activation pathway were well characterized. Based on these results, we postulated a consistent mechanism for ETH activation, not involving sulfinic acid as a precursor of the iminoyl radical, as proposed so far, but putting forward a novel reactivity for the S-oxide ethionamide intermediate. We proposed that ETH is first oxidized into S-oxide ethionamide, which then behaves as a “ketene-like” compound via a formal [2 + 2] cycloaddition reaction with peroxide to give a dioxetane intermediate. This unstable 4-membered intermediate in equilibrium with its open tautomeric form decomposes through different pathways, which would explain the formation of the iminoyl radical and also that of different metabolites observed for ETH oxidation, including the ETH–NAD active adduct. The elucidation of this unprecedented ETH activation mechanism was supported by the application of isotopic labelling experiments.
A step-economical multicomponent synthesis of 3D-shaped aza-diketopiperazines and their drug-like chemical space analysis by Pierre Regenass; Stéphanie Riché; Florent Péron; Didier Rognan; Marcel Hibert; Nicolas Girard; Dominique Bonnet (8859-8863).
A rapid and atom economical multicomponent synthesis of complex aza-diketopiperazines (aza-DKPs) driven by Rh(i)-catalyzed hydroformylation of alkenylsemicarbazides is described. Combined with catalytic amounts of acid and the presence of nucleophilic species, this unprecedented multicomponent reaction (MCR) enabled the formation of six bonds and a controlled stereocenter from simple substrates. The efficacy of the strategy was demonstrated with a series of various allyl-substituted semicarbazides and nucleophiles leading to the preparation of 3D-shaped bicyclic aza-DKPs. Moreover, an analysis of their 3D molecular descriptors and “drug-likeness” properties highlights not only their originality in the chemical space of aza-heterocycles but also their great potential for medicinal chemistry.
Modular access to vicinally functionalized allylic (thio)morpholinonates and piperidinonates by substrate-controlled annulation of 1,3-azadienes with hexacyclic anhydrides by Hannah Braunstein; Spencer Langevin; Monique Khim; Jonathan Adamson; Katie Hovenkotter; Lindsey Kotlarz; Brandon Mansker; Timothy K. Beng (8864-8872).
A modular substrate-controlled hexannulation of inherently promiscuous 1,3-azadienes with hexacyclic anhydrides, which affords versatile vicinally functionalized allylic lactams, in high yields, regio- and stereoselectivities is described.
Visible light dye-photosensitised oxidation of pyrroles using a simple LED photoreactor by James K. Howard; Kieran J. Rihak; Christopher J. T. Hyland; Alex C. Bissember; Jason A. Smith (8873-8880).
The photooxidation of pyrrole is typically low yielding due to the absorbance of ultraviolet light, which leads to uncontrolled polymerisation and decomposition. Presented herein is the development of a simple and cost-effective photoreactor utilising Light Emitting Diodes (LEDs) as the light source, and its application to the dye-sensitised oxidation of a range of pyrroles to give corresponding 3-pyrrolin-2-ones. The broader applicability of this approach to the generation of 1O2 is also explored.
Back cover (8881-8882).