A transition-metal-catalyzed enediyne cycloaromatization

The pentamethylcyclopentadienyl iron cation, generated from [(eta5-C5Me5)Fe(NCMe)3]PF6, triggers the room temperature cycloaromatization of acyclic and alicyclic enediynes, in the presence of either 1,4-cyclohexadiene or terpinene as the hydrogen-atom donor, to give metal-arene products in good to excellent yields. Photolysis of the metal-arene complexes liberates the arene from the metal in excellent yield. The first demonstration of a transition-metal-catalyzed cycloaromatization of conjugated enediynes has been achieved under photochemical conditions utilizing either [(eta5-C5Me5)Fe(NCMe)3]PF6 or [(eta5-C5Me5)Fe(eta6-1,2-(Prn)2C6H4)]PF6 as the catalyst precursor. The use of a metal and light has led to a convenient method for cycloaromatization of a trans-enediyne.     

Role of steric effects in protein-directed enediyne cycloaromatization of neocarzinostatin

The antibiotic neocarzinostatin comprises a carrier protein with a well-defined cavity for accommodating an active enediyne chromophore. The protein has two disulfides, one (Cys(37)-Cys(47)) lies on the cavity bottom and the other (Cys(88)-Cys(93)) in a constrained short loop. When the chromophore is not bound to the protein, a thiol-induced cycloaromatization of the enediyne into a tetrahydroindacene derivative is responsible for the potent antitumor activity. When it is protein-bound, the protein diverts the cycloaromatization pathway to form a distinct hydroxyisochromene-type product. How the protein directs the enediyne chemistry is an interesting puzzle, and various suggestions have been proposed in the past. We screened more than fifty thiols and manipulated conditions to locate reaction features and search for factors that could influence the protein directing strength. Thiol- and oxygen-concentration-dependence studies suggested that disulfides, which maintain the steric rigidity of the protein, could play a key role in diverting the cycloaromatization pathway. For direct proofs, we made mutations at each of the two disulfides by replacing sulfur atoms with oxygen. Circular dichroism and two-dimensional NMR spectroscopy studies suggested that the mutations changed neither the protein conformation nor the ligand interactions. Analyses of the thiol-induced cycloaromatization revealed that rupture of Cys(37)-Cys(47) made the protein almost completely lose its chemical directing ability, whereas rupture of Cys(88)-Cys(93) had only a minor influence. The results demonstrated that the steric rigidity of the binding cavity, but not necessary the whole protein, played an important role in the protein-directed mechanism.     

Palladium-catalyzed cycloaromatization polymerization of enediynes

Bergman cyclization has shown great promise in constructing conjugated polymers.However,the application of this reaction in polymer science is still limited due to the harsh reaction condition and ill-defined structure of the achieved polymers.To this end,the cycloaromatization polymerization of enediynes catalyzed by a series of transition metal catalysts is investigated in this work,by taking advantage of the coordination chemistry of the enediyne with the transition metal complexes.According to the nuclear magnetic resonance (NMR),Fourier transform infrared (FTIR),ultraviolet-visble (UV-Vis) spectroscopies and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis,the cycloaromatization polymerization of enediynes proceeds under milder conditions and in a more controlled manner in the presence of palladium(Ⅱ) complexes,giving structurally regulated conjugated polymers in high yields.     

Photoinduced Bergman cycloaromatization of imidazole-fused enediynes

A series of 4,5-bis-(alkyn-1-yl)imidazoles—‘imidazole-fused’ enediynes—were synthesized and their reactivities in photoinduced Bergman cycloaromatization reactions were determined. The more conformationally rigid analogues gave cycloaromatized products in good yields upon irradiation (450 W low-pressure mercury lamp, ambient temperature). A bicyclic analogue (3) was shown to cleave supercoiled plasmid DNA.     

Synthesis and cycloaromatization of a cyclic enyne-allene prodrug

A simple and stable cyclic enediynone (4) has been synthesized using an intramolecular Nozaki-Hiyama-Kishi cyclization as the key step. Reaction with a thiolate nucleophile led to rapid cycloaromatization of 4. Trapping experiments using 1,4-cyclohexadiene support the intermediacy of an aromatic diradical in the cycloaromatization.     

Anionic cyclization of a cross-conjugated enediyne

Cross-conjugated enediynes cannot follow the Bergman cycloaromatization as it involves a methylenediyne moiety with only five pi e(-), insufficient for aromatization. Under reductive conditions the cyclization is made feasible by generating a product with a Hückel number of pi electrons. We illustrate this principle and demonstrate for the first time an anionic cyclization of a cross-conjugated enediyne that results in formation of a five-membered ring. 9-(3-Phenyl-1-phenylethynylprop-2-ynylidene)-9H-fluorene (3) was reduced by potassium to yield the dianion of 9-(3,4-diphenylcyclopenta-2,4-dienylidene)-9H-fluorene (4(2-)), which contains a cyclopentadienyl fragment, and oxidation with iodine yielded the unstable fulvalene 4.     

Tellurium-mediated cycloaromatization of acyclic enediynes under mild conditions

The cycloaromatization of acyclic enediynes typically requires very high temperatures (>160 degrees C) and dilute conditions to proceed in a synthetically useful yield. These conditions hinder reaction throughput, inhibiting the use of this reaction for the large-scale production of materials. The reaction of sodium telluride with acyclic arenediynes yields the corresponding tellurepine, which under gentle heating extrudes Te degrees to yield the cycloaromatization product. We have developed conditions that form sodium telluride from inexpensive tellurium metal in situ, and that also perform the desilylation of silylated arenediynes in the same process. Under our conditions, we are able to perform desilylation and cycloaromatization at temperatures as low as 40 degrees C and on a scale as large as 5 g in standard laboratory glassware.     

Syntheses of stereochemically diverse nine-membered ring-containing biaryls

[reaction: see text] A library of nine-membered, biaryl-containing rings has been synthesized in parallel on polystyrene macrobeads. Dimeric medium rings were shown to be accessible via a regio- and stereoselective double cyclization.     

Two-photon photochemical generation of reactive enediyne

p-Quinoid cyclopropenone-containing enediyne precursor (1) has been synthesized by monocyclopropanation of one of the triple bonds in p-dimethoxy-substituted 3,4-benzocyclodeca-1,5-diyne followed by oxidative demethylation. Cyclopropenone 1 is stable up to 90 degrees C but readily produces reactive enediyne 2 upon single-photon (Phi(300)(nm) = 0.46) or two-photon (sigma(800 nm) = 0.5 GM) photolysis. The photoproduct 2 undergoes Bergman cyclization at 40 degrees C with the lifetime of 88 h.     

N-substituent effect on the cis-trans geometry of nine-membered lactams

The cis-trans geometry of a nine-membered lactam significantly depends on the N-substituents; N-acyl-1-aza-2-cyclononanones (1a-c) exist as cis form; in contrast, N-Z- 1-aza-2-cyclononanone (1d) exists as trans form both in the crystal and in solution.     

Protein-degrading enediynes: library screening of Bergman cycloaromatization products

[structure: see text] A screening method based on Bergman cycloaromatization products was applied to a compact library of estrogenic-enediyne hybrids. An enediyne candidate identified from the screen was subsequently synthesized, and it induced temperature- and concentration-dependent degradation of human estrogen receptor alpha upon cycloaromatization.     

Perylene synthesis by the parallel cycloaromatization of adjacent enediynes

As part of an investigation into new synthetic routes to poly(peri-naphthalene), the synthesis and cycloaromatization of tetraethynylbiphenyls is described. The temperature-dependent cyclization of biphenyls containing unsubstituted alkynes provides the desired perylene in good yield.     

Ambient temperature activation of haloporphyrinic-enediynes: electronic contributions to bergman cycloaromatization

We have synthesized the nickel(II) 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins with -Br (2a) or -I (2b) at the alkyne termini position from the corresponding 2,3-diethynyl analogue (1). The cross coupling of nickel(II) 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with trimethyl(trimethylstannanylethynyl)silane in the presence of a Pd0 catalyst and subsequent deprotection with base under aqueous conditions yields the nickel(II) 2,3-diethynyl-5,10,15,20-tetraphenylporphyrin (1). Subsequent reaction of 1 with N-bromo- or N-iodosuccinimide in dry acetone in the presence of AgNO3 yields 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins in 70% (2a) and 68% (2b) yields. The X-ray crystal structures of 2a,b show that the porphyrin backbone deviates significantly from planarity due to a Ni(II)-induced mixture of the classic ruffle and saddle distortions. Thermolysis of 2a at 190 degrees C for 6 h in chlorobenzene and 30-fold 1,4-cyclohexadiene (CHD) generates the Bergman cyclized nickel(II) dibromopicenoporphyrin product (3) in 65% yield, which derives from diradical addition across the adjacent meso-phenyl substituents. Similarly, nickel(II) 2,3-bis(iodoethynyl)-5,10,15,20-tetraphenylporphyrin, 2b, cyclizes at 190 degrees C in chlorobenzene/CHD via high-temperature substitution of iodine by hydrogen (from CHD) or chlorine (from solvent) to afford a mixture of 4 (15%) and 5 (45%). Remarkably, ambient temperature incubation of 2a in MeOH/CHCl3 (1:3, 22 h) or chlorobenzene/CHD (3:1, 24 h) leads to generation of 3 in 15% and 22% isolated yields, respectively. Addition of 1.2 equiv of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in CHCl3/MeOH dramatically accelerates the rate of reaction, producing 3 in 30% yield within 0.5 h. The origin of the ambient temperature activation of 2a derives from the ability of electron-withdrawing functionalities at the alkyne termini to decrease the activation barrier to the Bergman product.     

Conformational control in activation of an enediyne

In the bicyclo[7.3.1]tridec-4-ene-2,6-diyne framework characteristic of calicheamicin, DFT calculations predict that the chair conformer should be much more reactive toward cycloaromatization compared to the boat form. A functionalized derivative of this framework with an added two-atom bridge to enforce the boat conformation was synthesized and shown to be stable at 23 degrees C. Cleavage of the bridge releases the conformational lock and cycloaromatization proceeds with t1/2 42.5 min/23 degrees C, presumably through the chair conformation. This confirms the prediction based on computation and points to a new principle for triggering the enediyne toxins.     

Synthesis of indenothiophenone derivatives by cycloaromatization of non-conjugated thienyl tetraynes

Non-conjugated thienyl tetrayne derivatives 1-3 are prepared as novel building block for the construction of indenothiophenone derivatives. Oxidation of 1-3, followed by cycloaromatization of the corresponding ketone derivatives 13-15 proceeds smoothly to afford indenothiophenone derivatives 16-21 in good yields.     

Uncialamycin, a new enediyne antibiotic

[structure: see text] Laboratory cultures of an undescribed streptomycete obtained from the surface of a British Columbia lichen produce uncialamycin (1), a new enediyne antibiotic. The structure of uncialamycin (1) has been elucidated by analysis of spectroscopic data. Uncialamycin (1) exhibits potent in vitro antibacterial activity against gram-positive and gram-negative human pathogens, including Burkholderia cepacia, a major cause of morbidity and mortality in patients with cystic fibrosis.     

Ruthenium-mediated cycloaromatization of acyclic enediynes and dienynes at ambient temperature

The ruthenium(II) cation, [Cp*Ru(NCMe)3]OTf (4), triggers the Bergman cycloaromatization of acyclic endiynes at room temperature in THF solvent. Treatment of 1,2-di(1-alkynynyl)cyclopentenes (13-Me, alkynyl = propynyl; 13-Prn, alkynyl = pentynyl; 13-Bui, alkynyl = 4-methyl-pent-1-ynyl) with 4 in THF solvent at room temperature gives rise to the ruthenium arene complexes: [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-5,6-dialkyl-1H-indene}]OTf (15-Me, alkyl = methyl, 64% yield; 15-Prn, alkyl = n-propyl, 73% yield; 15-Bui, alkyl = 4-methyl-1-pentynyl, 88% yield). In a similar fashion, the room-temperature reaction of 4 with 1-ethynyl-2-(1-propynyl)cyclopentene (11) and [2-(1-propynyl)-1-cyclopenten-1-yl]trimethylsilane (14) leads to the formation of [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-5-methyl-1H-indene}]OTf (12, 92% yield) and [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-6-methyl-1H-inden-5-yl)trimethylsilane}]OTf (16, 77% yield), respectively. The bis(TMS)-substituted enediyne (1-cyclopentene-1,2-diyldi-2,1-ethynediyl)bis(trimethylsilane) (9-TMS) and 4 underwent reaction at 100 degrees C to give [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-1H-inden-5-yl)trimethylsilane}]OTf (10, 69% yield). Deuterium-labeling studies rule out a mechanism that involves a ruthenium-vinylidene intermediate, and provide support for the involvement of a p-benzyne intermediate. In a similar fashion, complex 4 is shown to trigger the cycloaromatization of the conjugated dienyne, 1-ethenyl-2-(1-pentynyl)cyclopentene (19), at room temperature in chloroform-d1 solvent to give [Cp*Ru{(3a,4,5,6,7,7a-eta)-2,3-dihydro-5-(1-propyl)-1H-indene}]OTf (20, 96% yield), with no deuterium enrichment. In the absence of ruthenium the thermal cyclization reactions of unsubstituted acyclic enediynes (Bergman cycloaromatization) and acyclic conjugated dienynes (Hopf cyclization) typically require elevated temperatures (150-250 degrees C). Complexes 10 and 15-Prn were characterized structurally by X-ray crystallography.     

Synthesis and reactivity of cinnoline-fused cyclic enediyne

A short and efficient synthesis of cinnoline-fused cyclic enediyne is reported. Richter cyclization of o-(1,3-butadiynyl)phenyltriazene produced 3-alkynyl-4-bromocinnoline. The Sonogashira coupling of the latter with 5-hexyn-1-ol was employed for the introduction of a second acetylenic moiety. The crucial cyclization step was achieved under Nozaki-Hiyama-Kishi conditions. Cinnoline-fused 10-membered ring enediyne is more reactive than corresponding carbocyclic analog and produces good yield of the Bergman cyclization product upon mild heating. This enediyne induces single-strand dDNA scissions upon incubation at 40 °C.     

Cyclononitols: a flexible synthetic approach towards nine-membered carbasugar analogues

A novel, concise, stereocontrolled approach to nine-membered carbasugar analogues (cyclononitols) from a bicyclo[4.3.1]deca-2,4-dien-10-one scaffold, harbouring a ‘locked’ cyclononane ring and latent functionalities, is described.     

Discovery of pentaene polyols by the activation of an enediyne gene cluster: biosynthetic implications for 9-membered enediyne core structures

The identification and characterization of enediyne polyketide synthases (PKSEs) revealed that PKSE-bound polyene is a common intermediate, while its subsequent tailoring steps to enediyne cores remain obscure. Herein, we report pentaene polyols 5–7 and cinnamic acid derivatives 8 and 9 biosynthesized from an activated enediyne biosynthetic gene cluster in Streptomyces sp. CB02130. The C-1027 pksE could partially complement production of these polyene polyols in a CB02130 mutant where the native pksE is inactivated. The yields of 5–7 were improved by increasing the cellular pool of l-Phe through either gene inactivation of a prephenate dehydrogenase WlsPDH or supplementation of l-Phe. A flexible ammonia lyase WlsC4 is responsible for biosynthesis of 8 and 9 from l-Phe. The co-localization of wlsPDH and PKSE gene cassette supports their close evolutionary relationships and an enediyne genome mining strategy using WlsPDH. These findings not only provide a facile approach to activate silent enediyne BGCs, but suggest that a polyene epoxide intermediate may be formed for construction of 9-membered enediyne macrocycles.

Production of three new pentaene polyols 5–7 by an activated enediyne gene cluster and their biosynthetic study suggest the presence of a polyene epoxide intermediate during the early steps of 9-membered enediyne core formation.