Carbocycloaddition Strategies for Troponoid Synthesis.

Tropone is the prototypical aromatic 7-membered ring, and can be found in virtually any undergraduate textbook as a key example of non-benzenoid aromaticity. Aside from this important historical role, tropone is also of high interest as a uniquely reactive synthon in complex chemical synthesis as well as a valuable chemotype in drug design. More recently, there has been growing interest in the utility of tropones for catalysis and material science. Thus, synthetic strategies capable of synthesizing functional tropones are key to fully exploiting the potential of this aromatic ring system. Cycloaddition reactions are particularly powerful methods for constructing carbocycles, and these strategies in turn have proven to be powerful for generating troponoids. The following review article provides an overview of strategies for troponoids wherein the 7-membered carbocycle is generated through a cycloaddition reaction. Representative examples of each strategy are also provided.

Synthesis of 7-azabicyclo[4.3.1]decane ring systems from tricarbonyl(tropone)iron via intramolecular Heck reactions.

The 7-azabicyclo[4.3.1]decane ring system, common to a number of biologically active alkaloids, was accessed from tropone (via its η4-diene complex with Fe(CO)3) in a short sequence of steps: 1) nucleophilic amine addition and subsequent Boc-protection, 2) photochemical demetallation of the iron complex, and 3) an intramolecular Heck reaction. Minor modifications to the protocol enabled access to the related 2-azabicyclo[4.4.1]undecane system, albeit in lower yield.

Discoveries and Syntheses of Highly Potent Antimalarial Troponoids.

Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate.

Total Synthesis of (+)-3-Deoxyfortalpinoid†F, (+)-Fortalpinoid†A, and (+)-Cephinoid†H.

3-Deoxyfortalpinoid F, fortalpinoid A, and cephinoid H are members of the Cephalotaxus diterpenoids class of natural products, which feature diverse chemical structures and valuable biological activities. We report herein the development of a diastereoselective Pauson-Khand reaction as an effective pathway to access the core tetracyclic skeleton, which is found widely in Cephalotaxus diterpenoids. Furthermore, we enabled the construction of the tropone moiety through a ring-closing metathesis/elimination protocol. Based on the developed strategy, asymmetric synthesis of the title compounds has been achieved for the first time.

π-Lewis-Base-Catalyzed Asymmetric Vinylogous Umpolung Reactions of Cyclopentadienones and Tropone.

We disclose that the carbonates of 4-hydroxy-2-cyclopentenones can form π-allylpalladium-based 1,2-carbodipoles, which isomerize to interesting η2 -Pd0 -cyclopentadienone complexes. Compared with the labile parent cyclopentadienone, the HOMO energy of the related η2 -complex was significantly raised via the back-bonding of Pd0 as a π-Lewis base, rendering the uncoordinated C=C bond an electron-richer dienophile in inverse-electron-demand aza-Diels-Alder-type reactions with diverse 1-azadienes. The vinylogous (aza)Morita-Baylis-Hillman or cross Rauhut-Currier addition to (imine)carbonyls or activated alkenes, respectively, was also realized to afford chiral [4+2] or [2+2] cycloadducts, respectively, after trapping the re-generated π-allylpalladium species. New C1 -symmetric ligands from simple chiral sources were developed, exhibiting high stereoselectivity even with racemic substrates via an unusual dynamic kinetic resolution process. Besides, tropone could be similarly activated by a Pd0 complex.

The Game of Electrons: Organocatalytic Higher-Order Cycloadditions Involving Fulvene- and Tropone-Derived Systems.

The great progress that took place in the field of higher-order cycloadditions involving fulvene- and tropone-derived systems in the last few years is astonishing. By application of organocatalytic activation modes, new higher-order reactivities have been identified and described in the literature. These approaches take advantage of the high reliability of organocatalysis, at the same time expanding its potential and paving new directions for its further evolution. In this Minireview, the progress in the field of organocatalytic higher-order cycloadditions involving fulvene- and tropone-derived systems is summarized and insights into mechanistic aspects of the developed reactivities are provided. Furthermore, the discussion on the nomenclatural issues related to cycloaddition reactions has been conducted and solutions to clarify the picture proposed.

Organocatalytic Enantioselective 1,3-Dipolar [6+4] Cycloadditions of Tropone.

A highly stereoselective 1,3-dipolar [6+4] cycloaddition towards bridged azabicyclo[4.3.1]decane scaffolds has been developed, reacting aldehydes, 2-aminomalonates and tropone under mild conditions in the presence of a chiral phosphoric acid catalyst. The scope is demonstrated for a series of aldehydes and 2-aminomalonates, and the reaction proceeds in high yields, >95:5 d.r. and up to 99 % ee. A series of transformations, as well as a mechanistic proposal, are presented.

Photochemical Approach to the Cyclohepta[b]indole Scaffold by Annulative Two-Carbon Ring-Expansion.

We report on the implementation of the concept of a photochemically elicited two-carbon homologation of a π-donor-π-acceptor substituted chromophore by triple-bond insertion. Implementing a phenyl connector between the slide-in module and the chromophore enabled the synthesis of cylohepta[b]indole-type building blocks by a metal-free annulative one-pot two-carbon ring expansion of the five-membered chromophore. Post-irradiative structural elaboration provided founding members of the indolo[2,3-d]tropone family of compounds. Control experiments in combination with computational chemistry on this multibond reorganization process founded the basis for a mechanistic hypothesis.

Synthesis of Aromatic Rings Embedded in Polycyclic Scaffolds by Triyne Cycloaddition: Competition between Carbonylative and Non-Carbonylative Pathways.

Cycloadditions have emerged as some of the most useful reactions for the formation of polycyclic compounds. The carbonylative cycloaddition of triynes can lead to carbonylative and non-carbonylative competitive pathways, each leading to the formation of an aromatic ring. We report herein the one-pot synthesis of fully- and unsymmetrically-substituted tetracyclic 6,5,7,5-troponic and 6,5,6,5-benzenoid scaffolds using pre-organized triynes showing the competition between these two pathways.

One hundred years of benzotropone chemistry.

This review focuses on the chemistry of benzo-annulated tropones and tropolones reported since the beginning of the 20th century, which are currently used as tools by the synthetic and biological communities.

Lanthanide DO3A-tropone complexes: efficient dual MR/NIR imaging probes in aqueous medium.

In this work, we describe a novel DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) based ligand with a chromophoric tropone coordinating sidearm (1). Ln3+ complexes of 1 have one inner sphere water molecule. The r1 relaxivity of Gd1 is similar to that of the commercial Gd-based MRI agents. The neutral O-donor atom of the tropone moiety slows down the water exchange rate by a factor of 3 compared to GdDOTA. In addition, Nd1 and Yb1 complexes exhibit significant NIR emission in aqueous solutions indicating that the tropone unit is an efficient sensitizer for these Ln3+-ions. Therefore, this new ligand is a promising platform for the design of Ln3+ based dual MR/optical imaging probes.

Synthesis of Substituted Tropones by Sequential Rh-Catalyzed [5+2] Cycloaddition and Elimination.

Highly substituted tropones are prepared from cycloheptatrienes derived from Rh-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and propargylic alcohols. The intermolecular [5+2] cycloaddition is highly regioselective for a variety of propargylic alcohols. Elimination of the cycloaddition products afforded various substituted tropones.

Rhodium(II)-catalyzed enantioselective synthesis of troponoids.

We report a rhodium(II)-catalyzed highly enantioselective 1,3-dipolar cycloaddition reaction between the carbonyl moiety of tropone and carbonyl ylides to afford troponoids in good to high yields with excellent enantioselectivity. We demonstrate that α-diazoketone-derived carbonyl ylides, in contrast to carbonyl ylides derived from diazodiketoesters, undergo [6+3] cycloaddition reactions with tropone to yield the corresponding bridged heterocycles with excellent stereoselectivity.

Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid.

Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structure-activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues is presented and the bioactivity of the synthetic compounds is discussed.

Synthesis, chiroptical properties and density functional theory calculations of 3,3'-biphenyl-2,2'-bitropone.

The synthesis of new bitropone derivatives, namely, 3,3'-biphenyl-2,2'-bitropone and 7,7'-biphenyl-2,2'-bitropone, are reported. Isolation of enantiomers arising from restricted rotation around the C-C bond connecting the tropone moieties was attempted by means of chiral high performance liquid chromatography (HPLC). No separation was obtained for 7,7'-biphenyl-2,2'-bitropone. For 3,3'-biphenyl-2,2'-bitropone, difficulties were encountered because of the low separation factor of the peaks and the presence of a rapid racemization process. However, quantitative chiroptical data on the antipodes were obtained by linking a circular dichroism (CD) spectrometer and a UV-vis spectrophotometric detector in series to the HPLC instrument. The analysis of the CD and UV-vis spectra in terms of absolute conformations was done with the help of theoretical calculations performed at the Density Functional Theory (DFT) level. The most stable conformations of the 3,3'-biphenyl-2,2'-bitropone in its ground state were obtained. Starting from these minimum energy conformations, it was possible to compute theoretical CD and UV absorption spectra that fit well with the experimental ones. From this comparison the absolute configuration to the antipodes was assigned. Finally, the effect of the presence of the two lateral phenyl substituents on the structure of the bitropone and hence on the CD spectrum is discussed.

Crystal structure of 2-(methyl-amino)-tropone.

The title compound, 2-(methyl-amino)-cyclo-hepta-2,4,6-trien-1-one, C8H9NO, crystallizes in the monoclinic space group P21/c, with three independent mol-ecules in the asymmetric unit. The planarity of the mol-ecules is indicated by planes fitted through the seven ring carbon atoms. Small deviations from the planes, with an extremal r.m.s. deviation of 0.0345 Å, are present. In complexes of transition metals with similar ligands, the large planar seven-membered aromatic rings have shown to improve the stability of the complex. Two types of hydrogen-bonding inter-actions, C-H⋯O and N-H⋯O, are observed, as well as bifurcation of these inter-actions. The N-H⋯O inter-actions link mol-ecules to form infinite chains. The packing of mol-ecules in the unit cell shows a pattern of overlapping aromatic rings, forming column-like formations. π-π inter-actions are observed between the overlapping aromatic rings at 3.4462 (19) Šfrom each other.

Shunting Phenylacetic Acid Catabolism for Tropone Biosynthesis.

Tropone is a seven-membered ring nonbenzenoid aromatic compound. It is the core structure of tropolonoids, which have various biological activities. In this study, a hybrid tropone biosynthetic pathway was designed by connecting phenylacetic acid (PAA) degradation with its biosynthesis and reconstituted in Escherichia coli. To simplify pathway construction and optimization, the use of E. coli endogenous genes was maximized and only three exogenous genes were employed. The entire pathway was divided into four modules: the endogenous shikimate pathway module, the hybrid PAA biosynthetic module, the endogenous PAA catabolic module and the heterogeneous tropone biosynthetic module. Efficiency of the PAA catabolic module was enhanced using PAA consumption rate as the indicator. Then, a single point mutation was introduced to inactivate the ALDH domain of PaaZ and the carbon flow was redirected toward tropone synthesis. Assembly of the full pathway led to de novo tropone production with the best titer of 65.2 ± 1.4 mg/L in shake flask experiment. This study provides a potential alternative for sustainable production of tropone and its derivatives.

Construction of Fused Tropone Systems Through Intramolecular Rh(I)-Catalyzed Carbonylative [2+2+2+1] Cycloadditon of Triynes.

"Tropone" is a non-benzenoid aromatic skeleton that can be found in a variety of natural products. This cyclohepta-2,4,6-trien-1-one skeleton appears simple, but there have been no straightforward ways to construct this molecular architecture. It is conceivable that this molecule can be constructed via a higher order cycloaddition of three acetylene units and CO, but such process was not known until we have discovered that the carbonylative [2+2+2+1] cycloaddition of triynes can take place in the presence of a Rh complex catalyst and CO. However, this highly challenging process is naturally accompanied by ordinary [2+2+2] cyclotrimization products, i.e., benzenes, as side products. A mechanistic study led to two competing processes wherein the critical CO insertion occurs either to a rhodacyclopentadiene intermediate (Path A) or a rhodacycloheptatriene intermediate (Path B). The DFT analysis of those two pathways disclosed that the Path A should be the one that yields the carbonylative [2+2+2+1] cycloaddition products, i.e., fused tricyclic tropones. A further substrate design, inspired by colchicine structure, led to the almost exclusive formation of a fused tetracyclic tropone from a triyne bearing 1,2-disubstituted benzene moiety in a single step and excellent yield.

Hydroxytropylium chloride: the first crystal structure of an unfunctionalized hydroxytropylium ion.

The crystal structure of hydroxytropylium chloride, C7H6OH+·Cl-, the hydrochloride salt of tropone, is described, which represents the first crystallographic characterization of an unfunctionalized hydroxytropylium ion. Crystals were obtained serendipitously from a sample of chlorotropylium chloride after partial hydrolysis. This highlights the role of hydroxytropylium ions as an intermediate in the hydrolytic decomposition of halotropylium halides to tropone. The solid-state structure consists of layers, in which the hydroxytropylium and chloride ions interact via both strong hydrogen bonds formed by the hydroxy protons and weaker hydrogen bonds formed by the tropylium protons to produce a two-dimensional network.