Total Synthesis of Dictyodendrins by the Gold‐Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles

In total and formal syntheses of dictyodendrins B, C, E, and F, the key step involved the direct construction of the pyrrolo[2,3‐c ]carbazole core by the gold‐catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki–Miyaura coupling), C2 (addition to an aldehyde), N3 (alkylation), and C5 positions (Ullman coupling) provided divergent access to dictyodendrins.     

Total Synthesis of Dictyodendrins A–F by the Gold-Catalyzed Cascade Cyclization of Conjugated Diyne with Pyrrole

The total synthesis of dictyodendrins A–F was achieved by using the gold(I)-catalyzed annulation of a conjugated diyne with N-Boc-pyrrole for direct construction of the pyrrolo[2,3-c]carbazole scaffold. Late-stage functionalization of the resulting pyrrolo[2,3-c]carbazole to introduce various substituents provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.     

Synthesis of Dihydroindolo[2,3‐c]carbazole as Potential Telomerase Inhibitor

The dictyodendrins A–E were the first marine natural products that show inhibition of telomerase. A versatile and convergent route was described for the synthesis of derivatives of these pyrrolo[2,3‐c]carbazole alkaloids as potential inhibitors of telomerase, by cyclotrimerization [2 + 2 + 2] of ruthenium‐catalyzed diynamides diarylacetylenes.     

Dictyodendrins A-E,the first telomerase-inhibitory marine natural products from the sponge Dictyodendrilla verongiformis

Five new alkaloids, dictyodendrins A-E (1-5), were isolated from the Japanese marine sponge Dictyodendrilla verongiformis as telomerase inhibitors. Their structures were elucidated by spectroscopic and chemical methods. Dictyodendrins are tyramine-based pyrrolocarbazole derivatives containing three or four p-hydroxybenzene groups. They inhibited telomerase completely at a concentration of 50 microg/mL.     

Coupling selectivity in the radical‐controlled oxidative polymerization of 4‐phenoxyphenol catalyzed by (1,4,7‐triisopropyl‐1,4,7‐triazacyclononane)copper(II) complex

Various effects on the coupling selectivity of the oxidative polymerization of 4‐phenoxyphenol catalyzed by (1,4,7‐triisopropyl‐1,4,7‐triazacyclononane)copper(II) halogeno complex [Cu(tacn)X₂] are described. With respect to the amount of the catalyst and the nature of the halide ion (X) of Cu(tacn)X₂, the coupling selectivity hardly changed. The Cu(tacn) catalyst possessed a turnover number greater than 1860. As the temperature of the reaction and the polarity of the reaction solvent were elevated, the C O coupling at the o‐position increased, but the C C coupling was not involved. For the polymerization in toluene at 80 °C, poly(1,4‐phenylene oxide), obtained as a methanol‐insoluble part, showed the highest number‐average molecular weight of 4000 with a melting point (T_m) of 195 °C. Only a slight change in the coupling selectivity was observed in the presence or absence of hindered amines as the base. Surprisingly, however, the C O selectivity decreased from 100 to 24% with less hindered amines, indicating that the selectivity drastically changed from a preference for C O coupling to a preference for C C coupling. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4792–4804, 2000     

Non‐empirical calculations of NMR indirect carbon–carbon coupling constants. Part 4: Bicycloalkanes

A systematic study of the one‐bond and long‐range J(C,C), J(C,H) and J(H,H) in the series of nine bicycloalkanes was performed at the SOPPA level with special emphasis on the coupling transmission mechanisms at bridgeheads. Many unknown couplings were predicted with high reliability. Further refinement of SOPPA computational scheme adjusted for better performance was carried out using bicyclo[1.1.1]pentane as a benchmark to investigate the influence of geometry, basis set and electronic correlation. The calculations performed demonstrated that classical ab initio SOPPA applied with the locally dense Dunning's sets augmented with inner core s‐functions used for coupled carbons and Sauer's sets augmented with tight s‐functions used for coupled hydrogens performs perfectly well in reproducing experimental values of different types of coupling constants (the estimated reliability is ca 1–2 Hz) in relatively large organic molecules of up to 11 carbon atoms. Additive coupling increments were derived for J(C,C), J(C,H) and J(H,H) based on the calculated values of coupling constants within SOPPA in the model bicycloalkanes, in reasonably good agreement with the known values obtained earlier on pure empirical grounds. Most of the bridgehead couplings in all but one bicycloalkane appeared to be essentially additive within ca 2–3 Hz while bicyclo[1.1.1]pentane demonstrated dramatic non‐additivity of ?14.5 Hz for J(C,C), +16.6 Hz for J(H,H) and ?5.5 Hz for J(C,H), in line with previous findings. Non‐additivity effects in the latter compound established at the SOPPA level should be attributed to the through‐space non‐bonded interactions at bridgeheads due to the essential overlapping of the bridgehead rear lobes which provides an additional and effective non‐bonding coupling path for the bridgehead carbons and their protons in the bicyclopentane framework. Copyright © 2003 John Wiley & Sons, Ltd.     

Gas‐phase functionalized carbon‐carbon coupling reactions catalyzed by Ni (II) complexes

Gas‐phase C―C coupling reactions mediated by Ni (II) complexes were studied using a linear quadrupole ion trap mass spectrometer. Ternary nickel cationic carboxylate complexes, [(phen)Ni (OOCR¹)]⁺ (where phen = 1,10‐phenanthroline), were formed by electrospray ionization. Upon collision‐induced dissociation (CID), they extrude CO₂ forming the organometallic cation [(phen)Ni(R¹)]⁺, which undergoes gas‐phase ion‐molecule reactions (IMR) with acetate esters CH₃COOR² to yield the acetate complex [(phen)Ni (OOCCH₃)]⁺ and a C―C coupling product R¹‐R². These Ni(II)/phenanthroline‐mediated coupling reactions can be performed with a variety of carbon substituents R¹ and R² (sp³, sp², or aromatic), some of them functionalized. Reaction rates do not seem to be strongly dependent on the nature of the substituents, as sp³‐sp³ or sp²‐sp² coupling reactions proceed rapidly. Experimental results are supported by density functional theory calculations, which provide insights into the energetics associated with the C―C bond coupling step.     

Oxidative Coupling Of 2-Alkyl-6,6-dimethylpentafulvenyl Anions

Cucl₂-Induced oxidative coupling of 2-(tert-butyl)-6,6-dimethylpentafulvenyl anion 9 predominantly takes place at C(7) and C(5) to give [7–7] and [7–5] coupling products 15 and 16 in 35 and 47% yields, respectively (Scheme 3) whose structures are elucidated from 1D- and 2D-NMR analysis. Compared with the product distribution observed for 6,6-dimethylpentafulvenyl anion 2 (Scheme 1), no coupling at C(2)/C(3) of 9 is observed. This means that, besides electronic effects, steric effect are also important in oxidative couplings of fulvenyl anions. The same couplings occur in the case of 2,3-bis(6,6-dimethylfulven-2-yl)-2,3-dimethylbutane dianion 10 as well but, due to electronic as well as conformational effects (Scheme 5), intermolecular coupling (to give polymers 17 , Scheme 4) is strongly favored over intermolecular coupling. Mechanisms explaining base-catalyzed isomerization 15a ? 15b ? 15c (Scheme 6) as well as isomerization 16a ? 16b (Scheme 7) are proposed.     

The structural dependence of 13C, 13C coupling constants in cyclopropanes

The smallest one-bond carbon—carbon coupling constants of cyclopropane derivatives have been measured for [1-¹³C]cyclopropane-1,1-dicarboxylic acid and cyclopropanecarboxylic acid. The ¹³C, ¹³C coupling constants of cyclopropylcarbinol have also been determined. The dependence of ¹J(CC) of the three-membered ring on different substituents and hybridization effects is evaluated. The carbon—carbon coupling constant of the unsubstituted cyclopropane is discussed on the basis of self-consistent perturbation theory (SCPT) and s character calculations (localized bond orbitals), and the results are compared with the experimental finding. It is shown that the ¹J (CC) can be interpreted by assuming a dual-pathway coupling mechanism.     

Total Synthesis,Stereochemical Assignment,and Biological Activity of Chamuvarinin and Structural Analogues

A highly stereocontrolled synthesis of (+)‐chamuvarinin has been completed in 1.5 % overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin–Anh control), followed by the two step activation/cyclization to close the C20–C23 2,5‐cis‐substituted tetrahydrofuran ring and a Julia–Kocienski olefination at C8–C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2 % overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness.     

Full four‐component relativistic calculations of the one‐bond 77Se–13C spin‐spin coupling constants in the series of selenium heterocycles and their parent open‐chain selenides

Four‐component relativistic calculations of ⁷⁷Se–¹³C spin–spin coupling constants have been performed in the series of selenium heterocycles and their parent open‐chain selenides. It has been found that relativistic effects play an essential role in the selenium–carbon coupling mechanism and could result in a contribution of as much as 15–25% of the total values of the one‐bond selenium–carbon spin‐spin coupling constants. In the overall contribution of the relativistic effects to the total values of ¹J(Se,C), the scalar relativistic corrections (negative in sign) by far dominate over the spin‐orbit ones (positive in sign), the latter being of less than 5%, as compared to the former (ca 20%). A combination of nonrelativistic second‐order polarization propagator approach (CC2) with the four‐component relativistic density functional theory scheme is recommended as a versatile tool for the calculation of ¹J(Se,C). Solvent effects in the values of ¹J(Se,C) calculated within the polarizable continuum model for the solvents with different dielectric constants (ε 2.2–78.4) are next to negligible decreasing negative ¹J(Se,C) in absolute value by only about 1 Hz. The use of the locally dense basis set approach applied herewith for the calculation of ⁷⁷Se–¹³C spin‐spin coupling constants is fully justified resulting in a dramatic decrease in computational cost with only 0.1–0.2‐Hz loss of accuracy. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis-driven mapping of the dictyodendrin alkaloids

The dictyodendrin alkaloids have been described as the first telomerase inhibitors of marine origin. As such they represent interesting lead compounds in the quest for small molecule inhibitors of this tumor-marker enzyme. Described herein is the preparation of a collection of dictyodendrin-like compounds that hinges on the formation of their indole subunit by reductive cyclization of appropriate keto-amide precursors mediated by low valent titanium. It is shown that the underlying concept can be extended from the synthesis of heterocycles to the preparation of phenol and aniline derivatives using oxo-acid, oxo-nitrile or oxo-lactam derivatives as the substrates; such arene formations can even be carried out in cascade. Exploratory studies into the closure of the B-ring of the dictyodendrins with the aid of electrophilic reagents such as Ph₃PAuCl/AgSbF₆ or I⁺ revealed the bias of these polycyclic heteroarenes to undergo unusual skeletal rearrangements. It is demonstrated that the individual dictyodendrins and analogues are capable of cleaving double stranded DNA under oxidative conditions, provided that they exhibit at least one unprotected phenol group in their periphery.     

Can One Assess the π Character of a C–C Bond with the Help of the NMR Spin–Spin Coupling Constants?

Measured one‐bond spin–spin coupling constants (SSCC) ¹J(CC) can be used to describe the nature of the C–C bond, provided one is able to separate the various coupling mechanisms leading to ¹J(CC). The Fermi‐contact (FC) term probes the first‐order density at the positions of the coupling nuclei, whereas the noncontact terms (the paramagnetic spin orbit (PSO) and the spin–dipole (SD) terms) probe the π character of the C–C bond (the diamagnetic spin orbit (DSO) term can mostly be neglected). A model is tested, in which the value of the FC(CC) term is estimated with the help of measured SSCCs ¹J(CH). The difference between the measured J(CC) and the estimated FC(CC) values, Δ(CC)=PSO(CC)+SD(CC)+DSO(CC), provides a semiquantitative measure of the π character of a C–C multiple bond. The applicability and limitations of this approach are discussed by partitioning the four Ramsey terms of the SSCC ¹J(CC) into one‐ and two‐orbital contributions. The FC, PSO, and SD terms of ¹J(CC) are explained and analyzed with regard to their relationship to other C–C bond properties. It is shown that empirical relationships between measured SSCCs and the s character of a bond need reconsideration.     

1,2‐, 1,7‐ and 1,12‐Dicarba‐closo‐dodecaborane(12) Derivatives Revisited by 13C NMR Spectroscopy and DFT Calculations. First Observation of Isotope‐Induced Chemical Shifts 1Δ10/11B(13C), and the Signs and Magnitudes of Coupling Constants 1J(13C,13C) and 1J(13C,11B)

The origin of broadening of ¹³C(carborane) NMR signals of 1,2‐, 1,7‐ and 1,12‐dicarba‐closo‐dodecaboranes(12) and several diphenylsilyl derivatives has been examined in detail and could be traced only partially to unresolved ¹³C–¹¹B spin‐spin coupling. Other contributions to the line widths arise from ¹³C–¹H dipole‐dipole interactions and, in particular, from isotope‐induced chemical shifts ¹Δ^10/11B(¹³C), observed here for carboranes for the first time. In the case of 1‐diphenylsilyl‐1,2‐dicarba‐closo‐dodecaborane(12), the coupling constant ¹J(¹³C,¹³C) = 9.3 Hz was measured in natural abundance of ¹³C. The small value of this coupling constant and its negative sign is predicted by calculations based on optimised structures [B3LYP/6‐311+G(d,p) level of theory] of the parent carboranes and 1‐silyl‐1,2‐dicarba‐closo‐dodecaborane(12) as a model compound [calcd. ¹J(¹³C,¹³C) = –10.5 Hz]. Calculated coupling constants ¹J(¹³C,¹¹B) are small (<7 Hz), in contrast to published assumptions, and of either sign, whereas ¹J(¹¹B,¹¹B) are all positive and range up to 15 Hz.     

13C NMR spectra of non-labelled and 15N-mono-labelled azo dyes

¹³C NMR spectra of four types of azo coupling products from benzenediazonium chloride have been measured and interpreted, viz. hydrazo compounds with an intramolecular hydrogen bond (3-methyl-1-phenylpyrazole-4,5-dione 4-phenylhydrazone), azo compounds without an intramolecular hydrogen bond (4-hydroxyazobenzene), azo compounds with an intramolecular hydrogen bond (2-hydroxy-5-tert-butylazobenzene) and an equilibrium mixture of both the tautomers of 1-phenylazo-2-naphthol. The absolute values of the J(¹⁵N¹³C) coupling constants have been determined by recording the spectra of the ¹⁵N isotopomers, and have been used, in some cases, for ¹³C signal assignment. A relationship has been found between the chemical shifts of the C-1′ to C-4′ carbons of the phenyl group (from the benzenediazonium ion) or the ¹J(¹⁵N¹³C) coupling constant, and the composition of the tautomeric mixture.     

About the structure of phosphorus ylids: Electron distribution and geometry

Using ¹³C-chemical shifts as a probe for the electronic environment of carbon centers, triphenylphosphoniomethanide, the model case of a “reactive” phosphorus ylid, was found to have much more zwitterion than PC double bond character (resonance structure 1a being dominant). Triphenylphosphonio-propenide (“triphenylphosphonium-allylid”), a “moderated” ylid, accumulates electron excess mainly at the α-carbon atom (resonance structure 6a being dominant) whereas triphenylphosphonio-ethenoate (formyl-methylene-triphenylphosphorane) and other “stabilized” ylids carry roughly equal fractions of negative charge at the α-carbon and the oxygen atom (resonance formulas a and b being of comparable importance). The one-bond C,H coupling constant of triphenylphosphonio-methanide ( 1 ) argues against a perfectly planar ylid center. The three-bond P,C coupling constants permit the assignment of endo- or exo-configurations to ylids having an allyl-type side-chain.     

Oxidative Coupling of 6,6-Dimethylpentafulvenyl Anion

Oxidative treatment of anion 11 (obtained by deprotonation of 6,6-dimethylpentafulvene 10 , Scheme 3) with CuCl₂ gives a very complex mixture of coupling products 13 (18%), 14 (16%), 15 (36%), 16 (5%), and 17 (6%) (Scheme 4 and Table 2). These results show that the reactive intermediate obtained by oxidation of 11 (which is believed to be the fulvenyl radical 12 ) has several reactive sites. According to the experiments, reactivity is decreasing in the series C(7) > C(2)/C(3) > C(5) > C(1)/C(4) (Table 2), while simple frontier-orbital considerations would suggest the sequence C(7) > C(5) > C(2)/C(3) > C(1)/C(4). The results suggest that SOMO-SOMO interaction of the approaching fulvenyl radicals 12 is the central effect governing regioselectivity and product distribution, while Coulomb and steric interactions are secondary effects (Table 4).     

N‐methyliminodiacetic acid as a simple and highly efficient ligand for palladium‐catalyzed Suzuki–Miyaura cross‐coupling of aryl chlorides

A simple, air‐stable, inexpensive and easily prepared molecule, N‐methyliminodiacetic acid (MIDA), is reported as a ligand for palladium‐catalyzed Suzuki–Miyaura cross‐coupling reaction of phenylboronic acid with aryl chlorides. The yield of the corresponding Suzuki coupling reaction is up to around 90% at both high temperature of 80°C and room temperature under ambient atmosphere. Copyright © 2015 John Wiley & Sons, Ltd.     

A 300 MHz NMR. Evidence for the Configuration of Roxburghine B

The 300 MHz ¹H-NMR. spectrum of the alkaloid Roxburghine B is completely analysed. The coupling constant values give evidence for the configuration, which is revised to epi-allo: H(3β), H(15α), H(20α) and C(18β).     

One‐Pot Tandem Photoredox and Cross‐Coupling Catalysis with a Single Palladium Carbodicarbene Complex

The combination of conventional transition‐metal‐catalyzed coupling (2 e^? process) and photoredox catalysis (1 e^? process) has emerged as a powerful approach to catalyze difficult cross‐coupling reactions under mild reaction conditions. Reported is a palladium carbodicarbene (CDC) complex that mediates both a Suzuki–Miyaura coupling and photoredox catalysis for C?N bond formation upon visible‐light irradiation. These two catalytic pathways can be combined to promote both conventional transition‐metal‐catalyzed coupling and photoredox catalysis to mediate C?H arylation under ambient conditions with a single catalyst in an efficient one‐pot process.