Transannular Cyclization Research Articles

A Nonaromatic Thiophene‐Fused Heptalene and Its Aromatic Dianion

AbstractHeptalene, a nonaromatic, bicyclic 12 π‐electron system with a twisted structure, is of great interest with regard to its potential Hückel aromaticity in the two‐electron oxidized or reduced forms. The synthesis of thiophene‐fused heptalene 5 from the reductive transannular cyclization of bisdehydro[12]annulene 4, and its solid‐state structure, which was confirmed by X‐ray crystallographic analysis, is presented. Chemical reduction of 5 readily generated the corresponding dianion, which was successfully isolated as [(K[2.2.2]cryptand)+]252−. The X‐ray crystallographic analysis of the dianion revealed a shallower saddle structure for the heptalene moiety and a lesser degree of bond alternation relative to 5. 1H NMR spectroscopy exposed the effect of a diamagnetic ring current on dianion 52−, which was corroborated by nucleus‐independent chemical shift (NICS) calculations. These results demonstrate that the heptalene dianion, containing 14 π‐electrons, does indeed exhibit pronounced degrees of Hückel aromaticity.

Insight into Transannular Cyclization Reactions To Synthesize Azabicyclo[X.Y.Z]alkanone Amino Acid Derivatives from 8-, 9-, and 10-Membered Macrocyclic Dipeptide Lactams.

An efficient method for synthesizing different functionalized azabicyclo[X.Y.0]alkanone amino acid derivatives has been developed employing electrophilic transannular cyclizations of 8-, 9-, and 10-membered unsaturated macrocycles to form 5,5-, 6,5-, 7,5-, and 6,6-fused bicylic amino acids, respectively. Macrocycles were obtained by a sequence featuring peptide coupling of vinyl-, allyl-, homoallyl-, and homohomoallylglycine building blocks followed by ring-closing metathesis. X-ray crystallographic analyses of the 8-, 9-, and 10-membered macrocyclic lactam starting materials as well as certain bicyclic amino acid products provided insight into their conformational preferences as well as the mechanism for the diastereoselective formation of specific azabicycloalkanone amino acids by way of transannular iodolactamization reactions.

Anti-trypanosomal cadinanes synthesized by transannular cyclization of the natural sesquiterpene lactone nobilin

Acid-catalyzed transannular cyclization of the germacrene-type sesquiterpene lactone nobilin 1 was investigated with the aim of obtaining new anti-trypanosomal cadinane derivatives. The reaction was regiospecific in all tested reaction conditions. Compounds were fully characterized by spectroscopic and computational methods, and the anti-trypanosomal activity was evaluated and compared to nobilin (IC50 3.19±1.69μM). The tricyclic derivative 11 showed most potent in vitro activity against Trypanosoma brucei rhodesiense bloodstream forms (IC50 0.46±0.01μM). Acid-catalyzed transannular cyclization of natural cyclodecadienes is an efficient strategy to generate new natural product derivatives with anti-protozoal activity.

Endophyte inspired chemical diversity from beta-caryophyllene

The natural product (−)-β-caryophyllene is considered as an ideal initiator to generate diverse scaffolds by transannular cyclization due to its macrocyclic structure and abundant availability in nature.

Total Synthesis of Indole Alkaloid Alsmaphorazine D

AbstractA concise total synthesis of rac‐alsmaphorazine D has been described for the first time. The efficient synthetic strategy features four key transformations: 1) a catalytic intramolecular oxidative cyclization for the δ‐lactamindole backbone; 2) an oxidative cyclic aminal formation for the hexahydropyrrolo[2,3‐b]pyrrole framework; 3) a transannular radical cyclization for the construction of the diazabicyclo[3.3.1]nonane structure; and 4) a one‐pot desilylation/double epimerization reaction that affirms the relative stereochemistry.

Total synthesis of indole alkaloid alsmaphorazine D.

A concise total synthesis of rac-alsmaphorazine D has been described for the first time. The efficient synthetic strategy features four key transformations: 1) a catalytic intramolecular oxidative cyclization for the δ-lactamindole backbone; 2) an oxidative cyclic aminal formation for the hexahydropyrrolo[2,3-b]pyrrole framework; 3) a transannular radical cyclization for the construction of the diazabicyclo[3.3.1]nonane structure; and 4) a one-pot desilylation/double epimerization reaction that affirms the relative stereochemistry.

Biosynthetically inspired divergent approach to monoterpene indole alkaloids: total synthesis of mersicarpine, leuconodines B and D, leuconoxine, melodinine E, leuconolam, and rhazinilam.

Inspired by their potential biosynthesis, we have developed divergent total syntheses of seven monoterpene indole alkaloids including mersicarpine, leuconodines B and D, leuconoxine, melodinine E, leuconolam, and rhazinilam, and one unnatural analogue with an unprecedented structural skeleton. The key steps involve a Witkop–Winterfeldt oxidative indole cleavage followed by transannular cyclization. The transannular cyclization product was then converted to the corresponding structural skeletons by pairing its functional groups into different reaction modes.

Phenylnitrene, Phenylcarbene, and Pyridylcarbenes. Rearrangements to Cyanocyclopentadiene and Fulvenallene

Flash vacuum thermolysis (FVT) of phenyl azide 29 as well as precursors of 2-pyridylcarbene 34 and 4-pyridylcarbene 25 affords phenylnitrene 30 (labeled or unlabeled), as revealed by matrix isolation electron spin resonance spectroscopy. FVT of 1-(13)C-phenyl azide 29 affords 1-cyanocyclopentadiene (cpCN) 32, which is exclusively labeled on the CN carbon, thus demonstrating direct ring contraction in phenylnitrene 30 without the intervention of cycloperambulation and 1,3-H shifts. However, the cpCN obtained by rearrangement of pyridyl-2-((13)C-carbene) 34 carries (13)C label on all carbon atoms, including the CN carbon. Calculations at the B3LYP/6-31G* level and in part at the CASSCF/6-31G* and CASPT2/cc-pVDZ//CASSCF(8,8)/cc-pVDZ levels support a new mechanism whereby 2-pyridylcarbene rearranges in part via 1-azacyclohepta-1,2,4,6-tetraene 36 to phenylnitrene, which then undergoes direct ring contraction to cpCN. Another portion of 2-pyridylcarbene undergoes ring expansion to 4-azacyclohepta-1,2,4,6-tetraene 42, which then by trans-annular cyclization affords 6-azabicyclo[3.2.0]cyclohepta-1,3,5-triene 43. Further rearrangement of 43 via the spiroazirine 44 and biradical/vinylnitrene 45 affords cpCN with the label on the CN group. An analogous mechanisms accounts for the labeling pattern in fulvenallene 60 formed by ring contraction of 1-(13)C-phenylcarbene 59 in the FVT of 1-(13)C-phenyldiazomethane 58.

Transformation of octadehydrodibenzo[12]annulene to benzonaphthopentalene by successive nucleophilic and electrophilic transannular cyclizations

A nucleophile-induced cyclization of octadehydrodibenzo[12]annulene derivative 1b was investigated. Treatment of 1b with BuLi gave fused 5–9-membered ring products, dibenzobicyclo[7.3.0]tetraenediynes 2a and 2b, formed via a single transannular cyclization reaction. The reason why double cyclization did not occur is ascribed to the structure of a plausible anionic intermediate in which a negative charge locates apart from the remaining triple bond carbons. The second cyclization did not take place even when once-isolated product 2b was treated with BuLi because of the higher reactivity toward a nucleophile of the fulvene moiety compared to the triple bonds. On the other hand, heating a chlorobenzene solution of 2b containing cyclohexa-1,4-diene gave products 3a–c possessing a benzonaphthopentalene framework via a Bergman cyclization pathway albeit in low yields after inter- or intramolecular hydrogen abstraction. Moreover, iodine-induced transannular cyclization of 2b afforded the corresponding diiodide 3d.

Mechanism of Chemical Degradation and Determination of Solubility by Kinetic Modeling of the Highly Unstable Sesquiterpene Lactone Nobilin in Different Media

The objective of this work was first to investigate the chemical degradation of the sesquiterpene lactone nobilin and determine its solubility under conditions of concurrent degradation for partially amorphous starting material; second, to determine the effect of biorelevant media used in the in vitro measurement of intestinal absorption on degradation and solubility of nobilin. Purely aqueous medium (aq-TMCaco ), fasted and fed state simulated intestinal fluid (FaSSIF-TMCaco and FeSSIF-TMCaco ), and two liposomal formulations (LiposomesFaSSIF and LiposomesFeSSIF ) with the same lipid concentration as FaSSIF-TMCaco and FeSSIF-TMCaco were used. Degradation products were identified by nuclear magnetic resonance and X-ray crystallography and the order of reaction kinetics was determined. Solubility was deduced with a mathematical model encompassing dissolution, degradation, and reprecipitation kinetics that took into account particle size distribution of the solid material. Degradation mechanism of nobilin involved water-catalyzed opening of the lactone ring and transannular cyclization resulting in five degradation products. Degradation followed first-order kinetics in aq-TMCaco and FaSSIF-TMCaco , and higher-order kinetics in FeSSIF-TMCaco and the two liposomal formulations, whereas degradation in the latter media was diminished. Solubility of nobilin increased in the order: aq-TMCaco < FaSSIF-TMCaco , < LiposomesFaSSIF < FeSSIF-TMCaco < LiposomesFeSSIF . Improvement of stability and solubility was consistent with the incorporation of the nobilin molecule into colloidal lipid particles. The developed kinetic model is proposed to be a useful tool for deducing solubility under dynamic conditions.

Concise and enantioselective total synthesis of (-)-mehranine, (-)-methylenebismehranine, and related Aspidosperma alkaloids.

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (-)-mehranine and (+)-(6S,7S)-dihydroxy-N-methylaspidospermidine. A late-stage dimerization of (-)-mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (-)-methylenebismehranine.

Elemental F2 with transannular dienes: regioselectivities and mechanisms.

Three reaction paths, namely, molecule-induced homolytic, free radical, and electrophilic, were modeled computationally at the MP2 level of ab initio theory and studied experimentally for the reaction of F2 with the terminal dienes of bicyclo[3.3.1]nonane series. The addition of fluorine is accompanied by transannular cyclization to the adamantane derivatives in which strong evidence for the electrophilic mechanism both in nucleophilic (acetonitrile) and non-nucleophilic (CFCl3 , CHCl3 ) solvents were found. The presence of KF in CFCl3 and CHCl3 facilitates the addition and substantially reduces the formation of tar products.

Dearomatization-induced transannular cyclization: synthesis of electron-accepting thiophene-S,S-dioxide-fused biphenylene.

The transannular cyclization of dehydroannulenes bearing several alkyne moieties in close proximity is a powerful synthetic method for producing polycyclic aromatic hydrocarbons. We report that the reactivity can be switched by the aromaticity of the ring skeletons fused with the dehydroannulene core. Thus, while thiophene-fused bisdehydro[12]annulene 1 was handled as a stable compound in the air at room temperature, the oxidation with m-chloroperbenzoic acid from the aromatic thiophene rings to the nonaromatic thiophene-S,S-dioxides induced the transannular cyclization, even at room temperature, which was completed within 1 day to produce the formal [2 + 2] cycloadduct 3. This is in stark contrast to the fact that the thermal cyclization of 1 itself required heating at 80 °C for 9 days for completion. Experimental and theoretical studies indicate that the oxidation of even one thiophene ring in 1 sufficiently decreases the activation barrier for the transannular cyclization that proceeds through the 8π and 4π electrocyclic reaction sequence. The thiophene-S,S-dioxide-fused biphenylene 3 thus produced exhibits a set of intriguing properties, such as a higher electron affinity (E1/2 = -1.17 V vs Fc and Fc(+)) and a stronger fluorescence (ΦF = 0.20) than the other relevant biphenylene derivatives, which have electron-donating and nonfluorescent characteristics.

4.2](2,2′)(2,2′)Biphenylophanetriyne: A Twisted Biphenylophane with a Highly Distorted Diacetylene Bridge

Biphenylophane 1 bridged by acetylene and diacetylene linkages was synthesized. X-ray analysis revealed its highly deformed diacetylene unit with a bond angle of 160°. Enantiomers of 1 resolved by chiral HPLC underwent facile racemization with an activation energy of 90.6 kJ mol(-1). Transannular cyclization of 1 was induced by heating to generate benzyne intermediate 8, which was intercepted by furan to give 9, and by treatment with bromine to give dibromodibenzopicene (10).

Formation of a new benzotriquinane skeleton via intramolecular photocycloaddition reactions of a phenylethynes moiety to a 1-cyanonaphthalene ring system

Photoirradiation of 1-cyano-2-(2,2-dicyano-5-phenylpentyn-4-yl)naphthalene and its analogues promotes sequential intramolecular [2π + 2π] photocycloaddition and cyclobutene ring opening to form benzocyclooctatetraenes, which are then transformed to benzotriquinanes in good yields via a photochemical transannular cyclization process.

Transannular cyclization of (4S,5S)-germacrone-4,5-epoxide under basic conditions to yield eudesmane-type sesquiterpenes.

Transannular cyclizations of germacrone-4,5-epoxide under acidic and thermal conditions have been reported in our previous study. However, this process gave the different and interesting results under basic conditions. (4S,5S)-Germacrone-4,5-epoxide (1) was treated under basic conditions to yield four products (2-5). Compound 2 was an isomer of 1--(4S,5S,9Z)-4,5-epoxygermacra-7(11),9-dien-8-one--and the remaining three compounds (3-5) were eudesmane-type derivatives. Compounds 4 and 5 are new compounds. The structures of the new compounds were determined using high resolution (HR)-MS, one dimensional (1D)-NMR, 2D-NMR and circular dichroism (CD) spectroscopic data. Products 3-5 had the same carbon skeleton as that of eudesmane-type compounds; however, these compounds showed different arrangement of isoprene units to the natural eudesmane-type sesquiterpenes.

Searching for radical intermediates and pathways implied in the biosynthesis of some polycyclic cembranoids. A new plausible mechanism for the origin of sinulanocembranolide A in the coral Sinularia gyrosa

The 3(2H)-furanone 11 underwent dimerisation to 13 (71%) via the captodative radical intermediate 12 on treatment with t-butyl hydroperoxide, but similar treatment of 5-episinuleptolide (5) failed to produce the natural product 7 via the presumed radical intermediate 8. In other attempts to generate 8, irradiation of a solution of 5 in benzene led only to the corresponding E-isomer 14, and treatment of 5 with Mn(OAc)3 in HOAc produced the acetate of the isomeric alcohol 15. However, when a solution of 5-episinuleptolide (5) in THF was reacted with samarium diiodide, a sequence of transannular ketyl radical-induced coupling reactions ensued leading to the ring fused compound 20 in 62% yield. From these experiments in vitro it is difficult to make the case for the involvement of carbon-centred radical intermediates suggested earlier, in the biosynthesis of some polycyclic norcembranoids. It is proposed that the ring system in the recently described sinulanocembranolide A (1) is derived in vivo by way of a novel (3+2) type (possibly 1,3-dipolar) transannular cyclisation from the enedione intermediate 23 produced from 5-episinuleptolide (5).

Increasing the Structural Span of Alkyne Metathesis

A new generation of alkyne metathesis catalysts, which are distinguished by high activity and an exquisite functional group tolerance, allows the scope of this transformation to be extended beyond its traditional range. They accept substrates that were previously found problematic or unreactive, such as propargyl alcohol derivatives, electron-deficient and electron-rich acetylenes of various types, and even terminal alkynes. Moreover, post-metathetic transformations other than semi-reduction increase the structural portfolio, as witnessed by the synthesis of a annulated phenol derivative via ring-closing alkyne metathesis (RCAM) followed by a transannular gold-catalyzed Conia-ene reaction. Further examples encompass a post-metathetic transannular ketone-alkyne cyclization with formation of a trisubstituted furan, a ruthenium-catalyzed redox isomerization, and a Meyer-Schuster rearrangement/oxa-Michael cascade. These reaction modes fueled model studies toward salicylate macrolides, furanocembranolides, and the cytotoxic macrolides acutiphycin and enigmazole A; moreover, they served as the key design elements of concise total syntheses of dehydrocurvularin (27) and the antibiotic agent A26771B (36).

A practical synthesis of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane

The rigid piperazine homologue 2,5-diazabicyclo[2.2.1]heptane (DBH) finds extensive application in medicinal chemistry and pharmaceutical research, but access to this scaffold is non-trivial. This letter details a concise synthetic sequence that gives ready access to DBH on gram scale. The route features a Staudinger reduction of an azide to facilitate a transannular cyclisation

An Iterative, Bimodular Nonribosomal Peptide Synthetase that Converts Anthranilate and Tryptophan into Tetracyclic Asperlicins

The bimodular 276kDa nonribosomal peptide synthetase AspA from Aspergillus alliaceus, heterologously expressed in Saccharomyces cerevisiae, converts tryptophan and two molecules of the aromatic β-amino acid anthranilate (Ant) into a pair of tetracyclic peptidyl alkaloids asperlicin C and D in aratio of 10:1. The first module of AspA activates andprocesses two molecules of Ant iteratively to generate a tethered Ant-Ant-Trp-S-enzyme intermediate on module two. Release is postulated to involve tandem cyclizations, in which the first step is the macrocyclization of the linear tripeptidyl-S-enzyme, by the terminal condensation (CT) domain to generate the regioisomeric tetracyclic asperlicin scaffolds. Computational analysis of the transannular cyclization of the 11-membered macrocyclic intermediate shows that asperlicin C is the kinetically favored product due to the high stability of a conformation resembling the transition state for cyclization, while asperlicin D is thermodynamically more stable.