Carbocyclic Ring Research Articles

Hydroxy-Directed Enantioselective Hydroxyalkylation in the Carbocyclic Ring of Indoles.

A Cinchona-derived squaramide catalyzes the reaction between hydroxyindoles and isatins leading to enantioenriched indoles substituted in the carbocyclic ring. The reaction proceeds efficiently with differently substituted isatins, yielding the desired products with excellent regioselectivity, good yields, and high enantiocontrol. Moreover, every position of the carbocyclic ring of the indole can be functionalized by using the appropriate starting hydroxyindole. The OH group was removed smoothly upon hydrogenolysis of the corresponding triflate.

Elucidation of the biosynthesis of the methane catalyst coenzyme F430.

SummaryMethane biogenesis in methanogens is mediated by methyl-coenzyme M reductase, an enzyme that is also responsible for the utilisation of methane through anaerobic methane oxidation. The enzyme employs an ancillary factor called coenzyme F430, a nickel-containing modified tetrapyrrole that promotes catalysis through a novel methyl radical/Ni(II)-thiolate intermediate. However, the biosynthesis of coenzyme F430 from the common primogenitor uroporphyrinoge III, incorporating 11 steric centres into the macrocycle, has remained poorly understood although the pathway must involve chelation, amidation, macrocyclic ring reduction, lactamisation and carbocyclic ring formation. We have now identified the proteins that catalyse coenzyme F430 biosynthesis from sirohydrochlorin, termed CfbA-E, and shown their activity. The research completes our understanding of how nature is able to construct its repertoire of tetrapyrrole-based life pigments, permitting the development of recombinant systems to utilise these metalloprosthetic groups more widely.

Structural diversity of anti-pancreatic cancer capsimycins identified in mangrove-derived Streptomyces xiamenensis 318 and post-modification via a novel cytochrome P450 monooxygenase

Polycyclic tetramate macrolactams (PTMs) were identified as distinct secondary metabolites of the mangrove-derived Streptomyces xiamenensis 318. Together with three known compounds—ikarugamycin (1), capsimycin (2) and capsimycin B (3)—two new compounds, capsimycin C (4) with trans-diols and capsimycin D (5) with trans-configurations at C-13/C-14, have been identified. The absolute configurations of the tert/tert-diols moiety was determined in 4 by NMR spectroscopic analysis, CD spectral comparisons and semi-synthetic method. The post-modification mechanism of the carbocyclic ring at C-14/C-13 of compound 1 in the biosynthesis of an important intermediate 3 was investigated. A putative cytochrome P450 superfamily gene, SXIM_40690 (ikaD), which was proximally localized to the ikarugamycin biosynthetic pathway, was characterized. In vivo gene inactivation and complementation experiment confirmed that IkaD catalysed the epoxide-ring formation reaction and further hydroxylation of ethyl side chain to form capsimycin G (3′). Binding affinities and kinetic parameters for the interactions between ikarugamycin (1) and capsimycin B (3) with IkaD were measured with Surface Plasmon Resonance. The intermediate compound 3′ was isolated and identified as 30-hydroxyl-capsimycin B. The caspimycins 2 and 3, were transferred to methoxyl derivatives, 6 and 7, under acidic and heating conditions. Compounds 1–3 exhibited anti-proliferative activities against pancreatic carcinoma with IC50 values of 1.30–3.37 μM.

Ligand-Enabled Alkynylation of C(sp3 )-H Bonds with Palladium(II) Catalysts.

The palladium(II)-catalyzed β- and γ-alkynylation of amide C(sp3 )-H bonds is enabled by pyridine-based ligands. This alkynylation reaction is compatible with substrates containing α-tertiary or α-quaternary carbon centers. The β-methylene C(sp3 )-H bonds of various carbocyclic rings were also successfully alkynylated.

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

AbstractThe palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp3)−H bonds is enabled by pyridine‐based ligands. This alkynylation reaction is compatible with substrates containing α‐tertiary or α‐quaternary carbon centers. The β‐methylene C(sp3)−H bonds of various carbocyclic rings were also successfully alkynylated.

Copper-catalyzed oxidative C(sp3)-H/C(sp2)-H cross-coupling en route to carbocyclic rings.

Copper-catalyzed selective coupling of C(sp3)-H bonds with C(sp2)-H bonds has been developed. An aniline module was used as a directing group to generate an aminyl radical, which selectively cleaves the secondary and tertiary C(sp3)-H bonds via a 1,5-HAT process to forge six-membered carbocyclic rings.

Study towards diversity oriented synthesis of optically active substituted cyclopentane fused carbocyclic and oxacyclic medium-sized rings: Competition between Grubbs-II catalyzed ring closing olefin metathesis and ring closing carbonyl-olefin metathesis

A study towards diversity-oriented synthesis of optically active cyclopentane fused bicyclic frameworks has been accomplished. The common intermediate was prepared from commercially available starting material (S)-carvone. The observations on competition between Grubbs-II catalyzed ring closing metathesis (RCM) and ring closing carbonyl-olefin metathesis (RCCOM) were the key features of the study.

The biosynthetic pathway of coenzyme F430 in methanogenic and methanotrophic archaea.

Methyl-coenzyme M reductase (MCR) is the key enzyme of methanogenesis and anaerobic methane oxidation. The activity of MCR is dependent on the unique nickel-containing tetrapyrrole known as coenzyme F430. We used comparative genomics to identify the coenzyme F430 biosynthesis (cfb) genes and characterized the encoded enzymes from Methanosarcina acetivorans C2A. The pathway involves nickelochelation by a nickel-specific chelatase, followed by amidation to form Ni-sirohydrochlorin a,c-diamide. Next, a primitive homolog of nitrogenase mediates a six-electron reduction and γ-lactamization reaction before a Mur ligase homolog forms the six-membered carbocyclic ring in the final step of the pathway. These data show that coenzyme F430 can be synthesized from sirohydrochlorin using Cfb enzymes produced heterologously in a nonmethanogen host and identify several targets for inhibitors of biological methane formation.

Facile and Regioselective Synthesis of Substituted 1H‐Pyrazolo[3,4‐b]quinolines from 2‐Fluorobenzaldehydes and 1H‐Pyrazol‐5‐amines

The present article concerns the scope and limitations of the regioselective condensation of 2‐fluorobenzaldehydes with 1H‐pyrazol‐5‐amines, leading to the synthesis of substituted 1H‐pyrazolo[3,4‐b]quinolines (PQ), in the presence of a base catalyst (DABCO and 2,4,6‐trimethylpyridine). A method to obtain these nitrogen heterocycles with fluorine or trifluoromethyl substituents in different positions in the carbocyclic ring was developed as a part of a systematic research on the influence of fluorine‐containing substituents on the parameters of PQ. Those compounds, characterized by high‐fluorescence intensity, have been tested as emitters for the organic light‐emitting diodes since 1997. The functionalization of PQ causes changes in various parameters, for example, HOMO and LUMO levels, which are important for the adjustment of fabricated organic light‐emitting diodes. One of the easiest methods of PQ preparation, namely, the condensation of substituted anilines with 5‐chloro‐1H‐pyrazole‐4‐carbaldehydes, is not regioselective. The method described in this study allows synthesizing of 1H‐pyrazolo[3,4‐b]quinolines with good yields and high selectivity – only the expected isomer is obtained. As various different 2‐fluorobenzaldehydes are commercially available, and 1H‐pyrazol‐5‐amines with different substituents are easy to prepare, the method could be a good alternative to the already known procedures. All possible mechanisms of the reaction were also thoroughly studied.

Fissitungfines A and B, two novel aporphine related alkaloids from Fissistigma tungfangense

Two novel aporphine related alkaloids, fissitungfines A (1) and B (2), together with two known biogenetically related alkaloids, nornuciferine (3) and annonaine (4), were isolated from the stems of Fissistigma tungfangense. Fissitungfines A (1) and B (2) were a new type of aporphine related alkaloids, possessing an unprecedented skeleton in which one six-membered carbocyclic ring in classic aporphine alkaloid was replaced by one six-membered lactone ring. Their structures were elucidated on the basis of spectroscopic data. A plausible biogenetic pathway for this new type of aporphine related alkaloid is also proposed.

Different acid-base behaviour of a pyrazole and an isoxazole with organic acids: crystal and molecular structures of the salt 3-(4-fluorophenyl)-1H-pyrazolium 2,4,6-trinitrophenolate and of the cocrystal 4-amino-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide-3,5-dinitrobenzoic acid (1/1).

Pyrazole and isoxazole rings differ only in the notional replacement of a potential hydrogen-bond-donor NH unit in pyrazole by a potential hydrogen-bond-acceptor O atom in isoxazole. It is thus of interest to compare the hydrogen-bonding characteristics of these rings. (4-Fluorophenyl)pyrazole undergoes protonation in the presence of 2,4,6-trinitrophenol to yield the salt 3-(4-fluorophenyl)-1H-pyrazolium 2,4,6-trinitrophenolate, C9H8FN2(+)·C6H2N3O7(-), (I), whereas there is no proton transfer between 4-amino-N-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide and 3,5-dinitrobenzoic acid, whose reaction gives the 1:1 cocrystal, C11H13N3O3S·C7H4N2O6, (II). The bond lengths in salt (I) provide evidence for aromatic-type delocalization in the pyrazolium ring and for extensive delocalization of the negative charge into the ring of the trinitrophenolate anion. The O atoms of one of the nitro groups in the trinitrophenolate anion are disordered over two sets of atomic sites having occupancies of 0.571 (6) and 0.429 (6), but all of the other substituents on the carbocyclic rings are fully ordered. The ions in salt (I) are linked by an extensive series of N-H...O hydrogen bonds to form a three-dimensional framework structure, and in cocrystal (II), the molecular components are linked by a combination of O-H...N and N-H...O hydrogen bonds to form complex bilayers. Comparisons are made with some related compounds.

Microwave-assisted organocatalysis: phosphine-mediated Tomita Zipper cyclization affording functionalized spirooxindole

A microwave-assisted and phosphine-mediated Tomita Zipper cyclization of dicyanomethylideneoxindoles and ynones has been developed. Various functionalized spirooxindoles with five-membered carbocyclic ring can be obtained in moderate to good yields with moderate to excellent diastereoselectivities through in situ generation of α-nucleophile (up to 87% yield, >20:1dr).

Synthesis of chiral five‐membered carbocyclic ring amino acids with an acetal moiety and helical conformations of its homo‐chiral homopeptides

Chiral five-membered carbocyclic ring amino acids bearing various diol acetal moieties were synthesized starting from l-malic acid, and homo-chiral homopeptides composed of cyclic amino acid (S)-Ac5 c(3EG) bearing an ethylene glycol acetal, up to an octapeptide, were prepared. A conformational analysis revealed that (S)-Ac5 c(3EG) homopeptides formed helical structures. (S)-Ac5 c(3EG) homopeptides, up to hexapeptides, formed helical structures without controlling the helical screw direction, while (S)-Ac5 c(3EG) hepta- and octapeptides formed helical structures with a preference for the left-handed (M) helical-screw direction. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 555-562, 2016.

Versatile Route to Benzoannulated Medium-Ring Carbocycles via Aryne Insertion into Cyclic 1,3-Diketones: Application to a Synthesis of Radermachol.

A general approach involving the insertion of in situ generated aryne into the C-C bond of cyclic 1,3-diketones for rapidly assembling functionalized benzo-fused medium ring carbocycles is delineated. The efficacy of the methodology has been demonstrated through a concise total synthesis of pentacyclic natural product radermachol.

Recent Advances in Discovery, Biosynthesis and Genome Mining of Medicinally Relevant Polycyclic Tetramate Macrolactams.

Polycyclic tetramate macrolactams (PTMs), a widely distributed class of structurally complex natural products exhibiting diverse biological activities, share a tetramate-containing macrocyclic lactam ring fused to a subset of carbocyclic rings. More than 30 naturally occurring PTM members have been reported. Representative members include ikarugamycin, HSAF, and alteramides. The emerging significance of PTMs in medicinal applications has raised attentions on their biosynthetic studies. These studies have unveiled the unexpected conservation of compact PTM biosynthetic loci in phylogenetically diverse bacteria and elucidated mechanisms for key steps in PTM biosynthesis. PTMs were demonstrated to be derived from the common origin of a hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) pathway, in which the PKS portion was iteratively used to generate two separate polyketide chains. A common tetramate-containing polyene intermediate was proposed to be the final product of all PTM PKS/NRPS assembly lines. Subsequently, a set of oxidoreductases acted in a not yet clearly understood way to dictate the manner of cyclizations to yield different polycycle ring systems in PTMs. The only well studied example was the formation of the inner fivemembered ring in ikarugamycin, which was catalyzed by an alcohol dehydrogenase via a [1 + 6] Michael addition. Nonetheless, these studies have illustrated the extraordinary simplicity of nature's art in the biosynthesis of PTMs with complex structures and paved the way to further expand the structural diversity of the family of medicinally relevant PTMs by genome mining and combinatorial biosynthesis.

ChemInform Abstract: Syntheses and Biological Studies of Marine Terpenoids Derived from Inorganic Cyanide

AbstractReview: 182 refs.

Organocatalytic Enantioselective Friedel–Crafts Aminoalkylation of Indoles in the Carbocyclic Ring

The first general catalytic method for the, so far elusive, enantioselective Friedel–Crafts functionalization of indoles in the carbocyclic ring is presented. This transformation contrasts with the usual tendency of these heterocycles to react at the azole ring. For this purpose, the four regioisomeric hydroxy carbocyclic-substituted indoles were reacted with several isatin-derived ketimines, using a Cinchona alkaloid-based squaramide, in a low 0.5–5 mol % catalyst loading, as a bifunctional catalyst. This methodology allows the functionalization of indoles in every position of the carbocyclic ring in a regio- and enantioselective fashion, by switching only the position of the hydroxy group in the starting material. Furthermore, several transformations were carried out, including the reductive elimination of the hydroxy group.

Strategies for the construction of morphinan alkaloid AB-rings: regioselective Friedel-Crafts-type cyclisations of γ-aryl-β-benzoylamido acids with asymmetrically substituted γ-aryl rings

The regioselectivity of the Friedel-Crafts-type cyclisation of a range of γ-aryl-β-benzoylamido acids, bearing oxy substituents at the C(3)- and C(4)-positions of the γ-aryl ring, has been investigated. In all of the cases examined (with 3,4-dimethoxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy substituents) the Lewis acid promoted cyclisation proceeds with exclusive regioselectivity for attack at the C(6)-position rather than at the C(2)-position, and furnishes the corresponding N- and O-protected 3-amino-6,7-dihydroxy-1-tetralone derivatives. This inherent regioselectivity can be overturned by the regioselective introduction of chlorine as a blocking group for the C(6)-position; subsequent Lewis acid promoted cyclisation then proceeds with exclusive regioselectivity for attack at the C(2)-position to deliver the corresponding N- and O-protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone derivative. These complementary cyclisation protocols represent useful methods for the preparation of these benzo-fused carbocyclic ring systems, which are the functionalised AB-rings of a range of morphinan alkaloids.

Understanding the Hydrodenitrogenation of Heteroaromatics on a Molecular Level

The cleavage of recalcitrant C–N linkages in heteroaromatic molecules is a critical component of hydrodenitrogenation (HDN) reactions, the processes by which N atoms are removed from crude fuels. C–N bond cleavage of heteroaromatics with traditional HDN catalysts such as sulfided Ni/Mo-Al2O3 and Ni/W-Al2O3 requires aggressive conditions to hydrogenate the heterocyclic rings and often unnecessarily saturates the carbocyclic rings as part of the C–N cleavage process. In contrast, small-molecule models have illustrated selective hydrogenation of the heterocyclic ring, providing mechanistic insight into HDN processes and inspiring the design of new, more selective HDN catalysts.

ChemInform Abstract: π‐Extended Pentalenes: The Revival of the Old Compound from New Standpoints

AbstractReview: [54 refs.