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The latent singlet diradical character of the parent ortho -quinonedimethide ( o -QDM), as revealed by valence bond calculations, is demonstrated experimentally by trapping with the kinetically stable free radical TEMPO at room temperature. In the absence of TEMPO, the main pathway for decomposition at ambient temperature is not (as previously proposed in the literature) a radical reaction but instead a concerted Diels-Alder dimerization, which through ωB97X-D/aug-cc-pVTZ/SMD//M06-2X-D3/6-31+G(d,p)/SMD calculations is shown to proceed through an ambimodal bispericyclic transition state. The predominantly non-radical reactivity of o -QDM at room temperature differs from that of its isomeric para -quinonedimethide ( p -QDM) congener, which self-reacts exclusively through radical pathways. These findings suggest the potential for tunable concerted/stepwise cycloadditions.

The two-electron reduction of 2,3-dimethylbuta-1,3-diene (DMB) with β-diketiminate and guanidinate substituted dimagnesium(I) compounds has given complexes in which two bidentate amido-magnesium fragments are bridged through the π-system of the DMB dianion, viz. [(LMg) 2 (μ-DMB)] (L= Xyl Nacnac, [HC(MeCNXyl) 2 ] - , Xyl=2,6-xylyl; or Priso=[(DipN) 2 CNPr i 2 ] - , Dip=2,6-diisopropylphenyl). Similar double reductions of [4]dendralene (4dend) have afforded the complexes, [(LMg) 2 (μ-4dend)] (L= Ar Nacnac, Ar=Xyl or mesityl (Mes); or Priso) in which the 4dend dianion is π-coordinated to the bidentate amido-magnesium fragments. Treatment of several such complexes with THF leads to Z- to E-isomerization of the dendralene fragment, and formation of purely σ-bonded Mg-C interactions in the THF coordinated products [{( Ar Nacnac)(THF)Mg} 2 (μ-4dend)] (Ar=Xyl, Mes or Dip). Reaction of myrcene (Myr) with [{( Xyl Nacnac)Mg} 2 ] proceeds via reductive coupling of Myr to give a previously unknown acyclic, branched C 20 tetra-olefin dianion complex [{( Xyl Nacnac)(THF)Mg} 2 (μ-Myr) 2 ]. Preliminary reactions of [(LMg) 2 (μ-DMB)] with H 2 and/or CO yielded a series of products, including novel magnesium hydride compounds, products derived from couplings of CO with the reduced DMB fragment (viz. magnesium dimethylcyclohexadienediolates), and one magnesium cyclopropanetriolate complex from the magnesium(I) induced coupling of DMB with H 2 and CO., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Cadiot-Chodkiewicz cross-couplings generate an unsymmetric buta-1,3-diyne by way of a Cu(I)-catalyzed coupling between a terminal alkyne and a 1-haloalkyne. Despite their widespread use, Cadiot-Chodkiewicz reactions are plagued by the generation of symmetric buta-1,3-diyne side products, formed through competing: (a) formal reductive homo-coupling of the 1-haloalkyne and (b) oxidative (Glaser-Hay/Eglinton) homo-coupling of the terminal alkyne. To overcome this issue, a large excess of one of the two reacting alkynes is commonly deployed, and difficult separations of cross- and homo-coupled products are often encountered. Here, we demonstrate that the use of ascorbate as a reductant leads to a suppression of these unwanted side reactions, hence permitting excellent yields with a roughly stoichiometric ratio of reactants. The procedure also avoids an inert gas atmosphere and uses a sustainable solvent. A similar approach is effective for cross-couplings involving a Pd(0)/Pd(II) catalytic cycle, with air tolerant Sonogashira couplings also established.

The diene-transmissive 2-fold Diels-Alder sequence between carbon-based dienophiles and [3]dendralenes is becoming an established method for polycarbocycle synthesis. Here, we demonstrate for the first time that imines are competent participants in intermolecular formal [4 + 2] cycloadditions with dendralenes. After a second Diels-Alder process with a carbadienophile, hexahydro- and octahydro-isoquinoline structures are formed. The formal aza-Diels-Alder reaction, which requires Lewis acid promotion, proceeds in high regio- and stereoselectivity under optimized conditions. ωB97XD/Def2-TZVP//M06-2X/6-31+G(d,p) calculations reveal a stepwise ionic mechanism for the formal aza-dienophile cycloadditions and also explain an unexpected Z → E olefin isomerization of a non-reacting C═C bond in the first formal cycloaddition.

The ground-state structure of the parent para -quinonedimethide ( p -QDM) molecule is generally represented in its closed shell form, i.e., as a cyclic, nonaromatic, through-conjugated/cross-conjugated hybrid comprising four C═C bonds. Nonetheless, p -QDM has been theorized to contain a contribution from its open-shell aromatic singlet diradical form. VBSCF calculations identify an open-shell contribution of 29% to the structure, while CASPT2(16,16)/def2-TZVP and ωB97XD/aug- cc -pVTZ calculations predict that dimerization proceeds along an open-shell singlet diradical pathway with a low (77 kJ/mol) barrier toward dimerization, which occurs by way of C-C bond formation between the exocyclic methylene carbons. A similar low (98 kJ/mol) barrier exists toward the reaction between a p -QDM molecule and the radical trap TEMPO. These predictions are verified experimentally through the isolation of bis -TEMPO-trapped p -QDM, its C-C coupled dimer, and by demonstrating that a mixture of p -QDM and TEMPO can initiate the radical polymerization of n -butyl acrylate at ambient temperature. In contrast to p -QDM, tetracyanoquinone (TCNQ) neither dimerizes nor reacts with TEMPO, despite having a similar diradical character to p -QDM. This lack of reactivity is consistent with both a higher kinetic barrier and a thermodynamically unfavorable process, which is ascribed to destabilizing steric clashes and polar effects.

The first general synthesis of branched tetraenes ([4]dendralenes) involves two or three steps from inexpensive, commodity chemicals. It involves an unprecedented variation on Suzuki-Miyaura cross-coupling, generating two new C-C bonds in a one-flask operation with control of diastereoselectivity. The broad scope of the method is established through the synthesis of more than 60 diversely substituted [4]dendralene molecules, along with substituted buta-1,3-dienes and other [ n ]dendralenes. [4]Dendralenes are demonstrated to be significantly more kinetically stable than their well-known [3]dendralene counterparts. The first stereoselective synthesis of these compounds is also reported, through the catalyst-controlled generation of both E - and Z -diastereomeric products from the same precursor. Novel, through-conjugated/cross-conjugated hybrid molecules are introduced. The first selective dienophile cycloadditions to substituted [4]dendralenes are reported, thus paving the way for applications in target-oriented synthesis.

The total synthesis of three diastereomeric matrine natural products is reported. The 8-step synthesis commences with simple acyclic precursors, forms all 4 rings of the tetracyclic natural product framework, and forges 10 of the 20 covalent bonds of the target structure. A cross-conjugated triene is positioned at the core of an acyclic branched structure. This precursor collapses to the tetracyclic natural product framework through an orchestrated sequence of two separate intramolecular cycloadditions. A subsequent, late-stage hydrogenation is accompanied by strain-release redox epimerizations to deliver the three natural products. An unprecedented carba-analogue is prepared in the same way. Semisynthetic manipulations of matrine provide access to 10 additional natural products.

Diene-transmissive hetero-Diels-Alder sequences involving carbonyl dienophiles are reported for the first time. High enantioselectivities are achieved in the reaction of phenylglyoxal with a broad range of dendralene structures, through the optimization of a Pd 2+ catalyst system. The initial catalyst-controlled enantioselective oxa-Diels-Alder (ODA) cycloaddition to a [3]dendralene generates a dihydropyran carrying a semicyclic diene. This participates in a subsequent catalyst or substrate-controlled Diels-Alder reaction to generate sp 3 -rich fused polycyclic systems containing both heterocycles and carbocycles. Computational investigations reveal a concerted asynchronous mechanism. π-Complexation of a diene C=C bond to Pd 2+ occurs in both the pre-transition state (TS) complex and in cycloaddition TSs, controlling stereoselectivity. A formal enantioselective [4+2]cycloaddition of a CO 2 dienophile is demonstrated., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The first broad spectrum investigation into the photoenolization/Diels-Alder (PEDA) sequence was carried out using M06-2X/6-31+G(d,p) in conjunction with SMD solvation and supported by experimental UV-vis spectroscopy. A test set of 20 prodienes was chosen to examine the role of the H atom acceptor group (substituted and unsubstituted carbonyl, thiocarbonyl, and imine), the H atom donor group, and bystander ring substituents. As reaction partners for the photogenerated dienes, a diverse test set of 20 dienophiles was examined, comprising electron rich, electron poor, neutral, strain activated, hydrocarbon, and heteroatom-containing molecules including CO 2 and CO. A key finding of this work is the demonstration that the PEDA sequence of carbonyl based prodienes is tolerant of most substitution patterns. Another is that thiocarbonyl derivatives should behave analogously to the carbonyls but are likely to do so much more slowly, due to an inefficient intersystem crossing, an endothermic 1,5-hydrogen atom transfer (HAT) step, and a [1,5] sigmatropic H shift to regenerate the starting material that outcompetes the [4 + 2]cycloaddition. In contrast, the T 1 state of the ortho -alkyl imines displays the incorrect orbital symmetry for 1,5-HAT and is correspondingly accompanied by higher barriers, even in the excited state. However, provided these barriers can be overcome, the remaining steps in the PEDA sequence are predicted to be facile. The Diels-Alder reaction is predicted to be of much broader scope than reported synthetic literature: while electron poor dienophiles are expected to be the most reactive partners, ethylene and electron rich alkenes should react at a synthetically useful rate. CO is predicted to undergo a facile (4 + 1)cheletropic addition instead of the normal [4 + 2]cycloaddition pathway. This unique photoenolization/cheletropic addition (PECA) sequence could provide metal-free access to benzannelated cyclopentanones.

A general synthetic approach to molecular structures that are hybrids of tetraethynylethylene (TEE) and tetravinylethylene (TVE) is reported. The synthesis permits the controlled preparation of many previously inaccessible structures, including examples with different substituents on each of the four branching arms. Most substituted TVE-TEE hybrids are found to be significantly more robust compounds than their unsubstituted counterparts, enhancing the prospects of their deployment in conducting materials and devices. Their participation in pericyclic reaction cascades, leading to sp 3 -rich polycycles, is demonstrated. The utilization of TEE-TVE hybrids as building blocks for larger acyclic, through/cross-conjugated hydrocarbon frameworks is also established. Aryl-substituted TEEs, TVEs, and their hybrids are fluorescent, with some exhibiting aggregation-induced emission enhancement. The structural requirements are defined and explained, setting the scene for applications as fluorescent probes and organic light-emitting diodes.

A concise synthesis of the alkaloid lythranidine is reported. The strategy exploits the target's local C 2 symmetry by adopting a two directional synthetic approach, first in an acyclic environment, then in a cyclic system and finally in a bridged macrocyclic domain. The latter phase of the synthesis, which installs all four stereocenters, involves a thermodynamically controlled, twofold intermolecular/transannular aza-Michael addition and a twofold hydride reduction. The synthesis is one third of the length of the most step-economic previous approach, providing access to gram quantities of the natural product. The broad-spectrum nature of the synthesis is demonstrated through the preparation of three diastereomeric analogues of the natural product., (© 2021 Wiley-VCH GmbH.)

A simple nonphotochemical procedure is reported for Cu(I)-catalyzed C-N coupling of aliphatic halides with amines and amides. The process is loosely based on the Goldberg reaction but takes place readily at room temperature. It uses Cu(I)Br, a commonly used and inexpensive atom transfer radical polymerization precatalyst, along with the cheap ligand N,N,N',N″,N″ -pentamethyldiethylenetriamine, to activate the R-X bond of the substrate via inner-sphere electron transfer. The procedure brings about productive C-N bond formation between a range of alkyl halide substrates with heterocyclic aromatic amines and amides. The mechanism of the coupling step, which was elucidated through application of computational methods, proceeds via a unique Cu(I) → Cu(II) → Cu(III) → Cu(I) catalytic cycle, involving (a) inner-sphere electron transfer from Cu(I) to the alkyl halide to generate the alkyl radical; (b) successive coordination of the N-nucleophile and the radical to Cu(II); and finally reductive elimination. In the absence of a nucleophile, debrominative homocoupling of the alkyl halide occurs. Control experiments rule out S N -type mechanisms for C-N bond formation.

There is a widespread perception that the high level of endo selectivity witnessed in many Diels-Alder reactions is an intrinsic feature of the transformation. In contrast to expectations based upon this existing belief, the first experimental Diels-Alder reactions of a novel, deuterium-labeled 1,3-butadiene with commonly used mono-substituted alkenic dienophiles (acrolein, methyl vinyl ketone, acrylic acid, methyl acrylate, acrylamide and acrylonitrile) reveal kinetic endo  :  exo ratios close to 1 : 1. Maleonitrile, butenolide, α-methylene γ-butyrolactone, and N -methylmaleimide behave differently, as does methyl vinyl ketone under Lewis acid catalysis. CBS-QB3 calculations incorporating solvent and temperature parameters give endo  :  exo product ratios that are in near quantitative agreement with these and earlier experimental findings. This work challenges the preconception of innate endo -selectivity by providing the first experimental evidence that the simplest Diels-Alder reactions are not endo -selective. Trends in behaviour are traced to steric and electronic effects in Diels-Alder transition structures, giving new insights into these fundamental processes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The first general preparative access to compounds of the 2,3-diethynyl-1,3-butadiene (DEBD) class is reported. The synthesis involves a one-pot, twofold Sonogashira-type, Pd 0 -catalyzed coupling of two terminal alkynes and a carbonate derivative of a 2-butyne-1,4-diol. The synthesis is broad in scope and members of this structural family are kinetically stable enough to be handled using standard laboratory techniques at ambient temperature. They decompose primarily through heat-promoted cyclodimerizations, which are impeded by alkyl substitution and accelerated by aryl or alkenyl substitution. An iterative sequence of these unprecedented Sonogashira-type couplings generates a new type of expanded dendralene. A suitably substituted DEBD carrying two terminal alkyne groups undergoes Glaser-Eglinton cyclo-oligomerization to produce a new class of expanded radialenes, which are chiral due to restricted rotation about their 1,3-butadiene units. The structural features giving rise to atropisomerism in these compounds are distinct from those reported previously., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Literature reports describe tetraethynylethylene (TEE) as unstable but tetravinylethylene (TVE) as stable. The stabilities of these two known compounds are reinvestigated, along with those of five unprecedented TEE-TVE hybrid compounds. The five new C 10 hydrocarbons possess a core, tetrasubstituted C═C bond carrying all possible combinations of vinyl and ethynyl groups. A unified strategy is described for their synthesis, whereupon cross-conjugated ketones are dibromo-olefinated then cross-coupled. Due to an incorrect but nonetheless widely held belief that acyclic π-bond rich hydrocarbons are inherently unstable, a standardized set of robustness tests is introduced. Whereas only TVE survives storage in neat form, all seven hydrocarbons are remarkably robust in dilute solution, generally surviving exposure to moderate heat, light, air, and acid. The first X-ray crystal structure of TEE is reported. Subgroups of hybrids based upon conformational preferences are identified through electronic absorption spectra and associated computational studies. These new acyclic π-bond rich systems have extensive, untapped potential for the production of stable, conjugated carbon-rich materials.

Readily available and stable substituted [3]dendralenes undergo highly chemo-, regio-, diastereo-, and enantioselective organocatalyzed Diels-Alder reactions with acrolein to form enantiomerically enriched cycloadducts. These monocycloadducts carry semicyclic dienes that undergo a second, substrate-controlled diastereoselective Diels-Alder reaction with a different dienophile to form 2-fold cycloadducts. Overall, annulated, functional group rich, chiral Δ 1(9) -octalin building blocks are accessed in one-pot operations that significantly extend the preparative value of diene-transmissive Diels-Alder sequences since they offer products of regio- and stereochemistry complementary to those generated from the parent, unsubstituted [3]dendralene.

The first chemical synthesis of tetravinylallene (3,5-divinylhepta-1,3,4,6-tetraene) is reported. The final, key step of the synthesis involves a palladium-catalyzed, Negishi-type cross-coupling involving 1,5-transposition of a penta-2-en-4-yn-1-ol methanesulfonate. The unprecedented fundamental hydrocarbon is sufficiently stable to be purified by flash chromatography. A similar synthetic pathway grants access to the first substituted tetravinylallenes, which provide insights into the influence of substitution upon stability and reactivity. Tetravinylallenes are shown to break new ground in swift structural complexity creation, with three novel sequences reported., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Diene-transmissive Diels-Alder (DTDA) sequences are extraordinarily powerful processes for the generation of fused bicyclic systems. Nonetheless, only stable dienophiles have previously been deployed. Herein we report DTDA sequences with a variety of substituted [3]dendralenes in the first study to deploy arynes as dienophiles. We demonstrate the one-flask generation of complex, aromatic-ring-containing, multicyclic systems of relevance to medicinal chemistry. These synthetic operations provide numerous successful examples of the otherwise challenging and rarely reported intermolecular Diels-Alder reaction of acyclic 1,3-butadienes with arynes, which is made possible due to the exalted reactivity of dendralenic dienes.

The first general synthetic approach to substituted [3]- and higher dendralenes is reported. Fifty-one mono- through to penta-substituted dendralenes carrying alkyl-, cycloalkyl-, alkenyl-, alkynyl-, aryl- and heteroaryl-substitutents are accessed, and the first ( E )/( Z )-stereoselective syntheses of dendralenes are reported (twenty-eight examples). The approach involves twofold Pd(0)-catalyzed Negishi couplings of 1,1-dibromoalkenes with alkenylzinc reagents, and exploits both substrate- and catalyst-controlled aspects of chemo-, regio- and stereoselectivity in the two C(sp 2 )-C(sp 2 ) bond forming steps. The value of the new hydrocarbons in rapid structural complexity generation is demonstrated through their deployment in unprecedented diene- and triene-transmissive pericyclic reaction sequences., (This journal is © The Royal Society of Chemistry 2019.)

The first general synthesis of compounds of the tetravinylethylene (TVE) family is reported. Ramirez-type dibromo-olefination of readily accessible penta-1,4-dien-3-ones generates 3,3-dibromo[3]dendralenes, which undergo twofold Negishi, Suzuki-Miyaura or Mizoroki-Heck reactions with a wide variety of olefinic coupling partners. This route delivers a broad range of unsymmetrically substituted tetravinylethylenes with up to three different alkenyl substituents attached to the central C=C bond. The extensive scope of the approach is demonstrated by the preparation of the first higher order oligo-alkenic through-conjugated/cross-conjugated hybrid compounds. An unsymmetrically substituted TVE is shown to undergo a domino electrocyclization-cycloaddition with high site-selectivity and diastereoselectivity, thereby demonstrating the substantial synthetic potential of substituted TVEs for controlled, rapid structural complexity generation., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: To determine in women with clinically stable chronic lung disease (CLD) and healthy women; (1) prevalence of urinary incontinence; (2) risk factors for urinary incontinence; (3) effects of a standard course of specialised physiotherapy treatment (PT) in women with CLD., Design: Prospective prevalence study; PT study in CLD subgroup., Setting: Tertiary metropolitan public hospital., Participants: Women with cystic fibrosis (CF, n=38), chronic obstructive pulmonary disease (COPD, n=27) and 69 healthy women without CLD. PT study - 10 women with CLD., Interventions: Five continence PT sessions over 3 months., Main Outcome Measures: Prevalence and impact of incontinence (questionnaire), number of leakage episodes (7-day accident diary), pelvic floor muscle function (ultrasound imaging) and quality of life (King's Health Questionnaire)., Results: The majority of women in all three groups reported episodes of incontinence (CF 71%; COPD 70%; healthy women 55%). Compared to age-matched healthy controls, women with CF reported more episodes of incontinence (P=0.006) and more commonly reported stress incontinence (P=0.001). A logistic regression model revealed that women with CLD were twice as likely to develop incontinence than healthy women (P=0.05). Women with COPD reported significantly more 'bother' with incontinence than age-matched women with incontinence. There was a significant reduction in incontinence episodes following treatment, which was maintained after three months., Conclusions: The presence of CLD is an independent predictor of incontinence in women. In older women this is associated with more distress than in age-matched peers without CLD. Larger treatment studies are indicated for women with CLD and incontinence., (Copyright © 2018 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Objectives: To identify urinary incontinence and its impact on men with stable chronic obstructive pulmonary disease (COPD) and men without lung disease., Design: Prospective questionnaire study., Setting: Outpatients attending a public metropolitan hospital., Participants: Men with COPD (n=49) and age-matched men without lung disease (n=36)., Interventions: Validated questionnaires to identify the prevalence and impact of urinary incontinence., Main Outcome Measures: Prevalence of urinary incontinence and relationship with disease-specific factors, and relationship of urinary incontinence with anxiety and depression., Results: The prevalence of urinary incontinence was higher in men with COPD (n=19/49) compared with men without lung disease (n=6/36; P=0.027). In men with COPD, symptoms of urgency were more prevalent in men with urinary incontinence (P=0.005), but this was not evident in men without lung disease (P=0.101). Only men with COPD reported symptoms of urgency associated with dyspnoea, and this did not vary between men with and without urinary incontinence (P=0.138). In men with COPD, forced expiratory volume in 1 second (FEV 1 ) was lower in those with urinary incontinence compared with those without urinary incontinence {mean 38 [standard deviation (SD) 14] % predicted vs 61 (SD 24) % predicted; P=0.002}. The impact of urinary incontinence did not differ between the two groups (P=0.333)., Conclusions: Incontinence is more prevalent in men with COPD than in men without lung disease. The prevalence of urinary incontinence increases with greater disease severity, as reflected by lower FEV 1 . Screening for urinary incontinence should be considered in men with COPD and compromised lung function., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

An extremely concise total synthesis of a potent phosphodiesterase-4 inhibitory natural product, selaginpulvilin D, is reported. The synthesis features a one-pot, 3-fold electrophilic aromatic substitution sequence to assemble a 9,9-diarylfluorene core. The approach allows access to useful quantities of a selaginpulvilin natural product for the first time.

Owing to the increased proton affinity that results from additional negative charges, multiply-charged anions have been proposed as one route to prepare and access a range of new and powerful "superbases". Paradoxically, while the additional electrons in polyanions increase basicity they serve to diminish the electron binding energy and thus, it had been thought, hinder experimental synthesis. We report the synthesis and isolation of the ortho -diethynylbenzene dianion ( ortho -DEB 2- ) and present observations of this novel species undergoing gas-phase proton-abstraction reactions. Using a theoretical model based on Marcus-Hush theory, we attribute the stability of ortho -DEB 2- to the presence of a barrier that prevents spontaneous electron detachment. The proton affinity of 1843 kJ mol -1 calculated for this dianion superbase using high-level quantum chemistry calculations significantly exceeds that of the lithium monoxide anion, the most basic system previously prepared. The ortho -diethynylbenzene dianion is therefore the strongest base that has been experimentally observed to date.

[Pd(PPh3 )4 ] catalyzes a Suzuki-Miyaura-like twofold cross-coupling sequence between underivatized propargylic diols and either aryl or alkenyl boronic acids to furnish highly substituted 1,3-dienes. Thus, 2,3-diaryl-1,3-butadienes and their dialkenic congeners ([4]dendralenes) are delivered in a (pseudo)halogen-free, single-step synthesis which supersedes existing methods. Allenols are also readily formed. Treatment of these single- and twofold cross-coupled products with acid leads to remarkably short syntheses of highly-substituted benzofulvenes and aryl indenes, respectively., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

1-Aminodecalins were prepared from acyclic precursors by combining the powerful twofold diene-transmissive Diels-Alder chemistry of [3]dendralenes with the simplicity of enamine formation. On mixing at ambient temperature, a simple dienal condenses with a primary or secondary amine to generate the enamine, a 1-amino-[3]dendralene in situ, and this participates as a double diene in a sequence of two Diels-Alder events with separate dienophiles. Overall, four C-C bonds and one C-N bond are formed. Mechanistic insights into these reactions are provided by means of density functional theory calculations., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first synthesis of all five possible monomethylated [4]dendralenes has been achieved via two distinct synthetic strategies. The Diels-Alder chemistry of these new dendralenes (as multidienes) with an electron poor dienophile, N-methylmaleimide (NMM), has been studied. Thus, simply upon mixing the dendralene and an excess of dienophile at ambient temperature in a common solvent, sequences of cycloadditions result in the rapid generation of complex multicyclic products. Distinct product distributions are obtained with differently substituted dendralenes, demonstrating that dendralene substitution influences the pathway followed, when a matrix of mechanistic possibilities exists. Dendralene site selectivities are traced to electronic, steric and conformational effects, thereby allowing predictive tools for applications of substituted dendralenes in future synthetic endeavors.

The [n]dendralenes are a family of acyclic hydrocarbons which, by virtue of their ability to rapidly generate structural complexity, have attracted significant recent synthetic attention. [3]Dendralene through [8]dendralene have been previously prepared but no higher member of the family has been reported to date. Here, we describe the first chemical syntheses of the "higher" dendralenes, [9]dendralene through [12]dendralene. We also report a detailed investigation into the spectroscopic properties and chemical reactivity of the complete family of fundamental hydrocarbons, [3]dendralene to [12]dendralene. These studies reveal the first case of diminishing alternation in behavior in a series of related structures. We also report a comprehensive series of computational studies, which trace this dampening oscillatory effect in both spectroscopic measurements and chemical reactivity to conformational preferences.

The [n]radialenes are a unique family of fundamental [n]-membered carbocyclic structures with radiating alkenes, which have attracted significant synthetic and theoretical attention. Whereas [3]-, [4]-, and [6]radialenes have been prepared and studied, all efforts to synthesize the five-membered ring compound have thus far met with failure. Here we describe the first synthesis of the fundamental hydrocarbon [5]radialene, C10H10. Our approach was a departure from previous radialene syntheses in that it utilized a low-temperature decomplexation of a stable organometallic compound, rather than high-temperature elimination or rearrangement. Our strategy was guided by analysis of previous radialene syntheses, which indicated rapid decomposition in oxygen, and ab initio calculations, which revealed an extraordinary susceptibility of [5]radialene to undergo Diels-Alder dimerization/polymerization. The origin of this susceptibility was traced to a small distortion energy associated with the formation of the transition structure geometry from the relaxed reactant monomers and to a narrow HOMO-LUMO gap.

The tetracarbocyclic framework of the nicandrenone natural products is formed in one step from a linear precursor via a domino intramolecular Diels-Alder/intramolecular furan Diels-Alder/aromatization sequence. The approach represents a new 0 → ABCD strategy for the preparation of aromatic steroids.

The two simplest branched acyclic structures comprising only conjugated C═C units, namely, [3]dendralene (3-methylene-1,4-pentadiene) and [4]dendralene (3,4-dimethylene-1,5-hexadiene), were first reported in 1955 and 1962, respectively. No higher members of the series were described in the literature until 2000. This Account describes the modern phase of dendralene chemistry, driven to a large extent by research performed within the author's group. The first synthesis of the parent dendralene family allowed access to the hydrocarbons in batches of up to 5 mg. The synthetic approach took into account the prevailing dogma of the time, specifically that these compounds would be very reactive species and hence difficult to handle in the laboratory. As such, a route involving the cheleotropic elimination of SO2 from stable, and generally insoluble, 3-sulfolene-masked precursors was devised. Our second-generation approach was of significantly higher value in preparative terms, allowing the syntheses of the first six members of the unsubstituted [n]dendralenes (i.e., n = 3-8) directly, on scales of hundreds of milligrams to decagrams, using commercially available precursors and standard laboratory equipment and methods. This work demonstrated that the assumed high reactivity and instability this family of compounds was erroneous and ultimately led to the development of syntheses of structurally related cross-conjugated systems including substituted dendralenes, tetravinylethylene, 1,1-divinylallene, and furan-containing analogues of the dendralenes. Cross-coupling reactions feature strongly in the syntheses of these compounds, and methods involving single- to multifold Stille, Kumada, and Negishi couplings are mainstays of this work. The even parity [n]dendralenes were shown to exhibit enhanced stability over the odd parity congeners, a result that can be attributed to conformational effects. π-Bond-rich branched hydrocarbons are demonstrated to have significant value in the rapid generation of structural complexity. Pericyclic processes are particularly useful in this regard, with the dendralenes and their relatives serving as multidienes, participating in diene-transmissive cycloaddition sequences, sometimes in combination with electrocyclizations, to generate fused and bridged multicyclic systems containing many new covalent bonds. The outcomes of exploratory investigations into pericyclic sequences involving dendralenes are presented, along with methods developed to control chemoselectivity, regioselectivity, and stereoselectivity. Distinct from their use in diene-transmissive sequences, the dendralenes also serve as multialkenes, for the direct synthesis of polyols and oligo-cyclopropanes. Finally, the deployment of π-bond-rich branched hydrocarbons in the shortest total synthesis of a pseudopterosin natural product is summarized, as a prelude to future prospects in the areas of hydrocarbon chemistry and target synthesis.

A measure of the strength of a synthetic strategy is its versatility: specifically, whether it allows structurally distinct targets to be prepared. Herein we disclose a unified approach for the total synthesis of natural products of three distinct structural types, all of which occur naturally as racemic mixtures. The point of divergence involves the terminal alkylation of a conjugated tetrayne, and culminates in a significantly shortened synthesis of endiandric acid A (8 steps), the first total synthesis of kingianic acid E (8 steps), and a second-generation synthesis of kingianins A, D, and F (11 steps). Evidence for redox catalysis in the biosynthesis of kingianic acid E is presented.

The pseudopterosin natural products have been the focus of a substantial number of synthetic studies since the first members were isolated almost 30 years ago. Herein we review all total and formal syntheses of this family of glycosylated diterpenes, with an emphasis on the synthetic strategies employed.

The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5-diaryl-3,4-dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels-Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6-31G(d) and M06-2X/6-31G(d) model chemistries., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The pseudopterosins are a family of diterpene marine natural products, which, by virtue of their interesting anti-inflammatory and analgesic properties, have attracted the attentions of many synthetic chemists. The most efficient syntheses reported to date are 14 and 20 steps in the longest linear sequence for chiral pool and enantioselective approaches, respectively, and all start with precursors that are easily mapped onto the natural product structure. Here, we describe an unconventional approach in which a chiral cross-conjugated hydrocarbon is used as the starting material for a series of three cycloadditions. Our approach has led to a significant reduction in the step count required to access these interesting natural products (10 steps chiral pool and 11 steps enantioselective). Furthermore it demonstrates that cross-conjugated hydrocarbons, erroneously considered by many to be too unstable and difficult to handle, are viable precursors for natural product synthesis.

Computational and experimental studies offer fresh insights into the neglected tetravinylethylene class of compounds. Both the structures and the outcomes of exploratory reactions of the parent hydrocarbon are predicted and explained in detail through high-level composite ab initio MO G4(MP2) computational studies.

Shallow methylene-bridged cavitands appended with simple H-bond donor/acceptor groups are shown to bind aspirin. The structural features needed in a synthetic receptor for aspirin binding are defined., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first four-fold cross coupling reaction involving alkenic partners leads to the title hydrocarbon on multi-gram scale in one step from commercially available precursors. In stark contrast to its close structural relatives, tetravinylethylene is a remarkably robust, bench-stable compound. The π-bond rich hydrocarbon is shown to undergo one-pot sequences of pericyclic reactions leading to the formation of complex systems with four new rings, seven C-C bonds and ten stereocenters with a very high level of stereoselectivity. Insights into the reactivity of this and related systems is provided using the accurate composite ab initio MO G4(MP2) method., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An examination of Diels-Alder reactions of furan-containing analogues of dendralenes has revealed complex and fascinating reaction sequences, which chart the inherent site and stereoselectivity of these processes and give rapid access to structures of high molecular complexity.

3-(Hydroxymethyl)xylitol, a compound reportedly isolated from the root of Casearia esculenta (Roxb.), along with its three possible stereoisomers, has been synthesized for the first time by way of a triple dihydroxylation reaction performed upon the simplest cross-conjugated hydrocarbon, [3]dendralene. The data for the natural product do not match any of the isomeric 3-(hydroxymethyl)pentitols. The structure of the natural product from the root of Casearia esculenta (Roxb.) has been corrected by reanalysis of the published data.

The first heteroatom-based dienophile cycloadditions to cross-conjugated alkenes ([n]dendralenes) are reported. Nitroso-dienophiles undergo smooth single and double Diels-Alder additions to the parent dendralenes with orientational regio- and stereoselectivity and, notably, with reactivity that depends upon the parity of the [n]dendralene. The first crystal structure of a cross-conjugated hexaene is reported. Vasella's nitroso-sugar reagent gives a highly enantiomerically enriched double cycloadduct with [3]dendralene. This bicyclic oxazine is successively dihydroxylated and then ring-opened to form a branched chain diamino tetrol.

The total synthesis of the racemic natural products (±)-incarviditone and (±)-incarvilleatone has been accomplished in three steps via biomimetic dimerization of (±)-rengyolone. Homochiral dimerization of (±)-rengyolone affords (±)-incarviditone through a domino oxa-Michael/Michael sequence. Heterochiral dimerization, involving a domino oxa-Michael/Michael/aldol reaction sequence, affords (±)-incarvilleatone. Single-crystal X-ray analysis of a derivative of (±)-incarviditone has resulted in revision of the originally proposed structure.

The first general synthesis of 1-substituted [3]dendralenes has led to the discovery that conjugating groups significantly enhance the rate of Diels-Alder dimerisation relative to both the parent [3]dendralene and to other substituted systems.

Twenty-seven years ago, H. Hopf published the only previous comprehensive review on branched oligoenes that had the title "Dendralenes: A Neglected Family of Hydrocarbons". The dendralenes are no longer neglected. Research into the synthesis, properties, and applications of dendralenes is rapidly gaining momentum and this Review summarizes important recent findings. From significant fundamental properties (the first demonstration of alternating behavior since the annulenes) through to unparalleled complexity-generating synthetic transformations, this fundamental oligoene family is coming of age. Effective synthetic approaches to cyclic and acyclic dendralene systems are analyzed and classified. The most powerful synthetic transformations of the dendralenes, diene-transmissive Diels-Alder reactions, are surveyed in detail., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

G4(MP2) calculations on Diels-Alder reactions of [3]- and [4]dendralene have revealed that reactant dendralene conformer populations and closed-shell singlet bis-pericyclic transition states explain their different reactivities., (This journal is © The Royal Society of Chemistry 2012)

[3]Dendralene and [4]dendralene are converted smoothly into tricarbonyliron complexes. The structures of four complexes analyzed by DFT and single-crystal X-ray analysis show that, in contrast to free hydrocarbons, complexed dendralenes prefer a roughly in-plane conformation. The complexes are stable towards Fe(CO)(3) group migration up to 150 °C. The synthetic value of Fe(CO)(3) complexation in the dendralene series is demonstrated through a variety of selective synthetic manipulations (Diels-Alder reaction, dipolar cycloaddition, Simmons-Smith cyclopropanation, dihydroxylation, olefin cross metathesis) that are not achievable by direct transformation of the free hydrocarbons. Application to the synthesis of a previously unreported, highly reactive linear/cross-conjugated hydrocarbon is also described., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)