Synthesis of the core structure of acutumine

[reaction: see text] The tricyclic core of the bioactive natural product acutumine has been synthesized. Key steps include an oxidative phenolic coupling to form a masked o-benzoquinone, an anionic oxy-Cope rearrangement to construct an all-carbon quaternary center, and a Michael-type cyclization to form an amine-bearing quaternary carbon. The target compound exists in solution as an enol, in contrast to related compounds that are ketones. A model explaining these observations is presented.     

Ionic vs pericyclic transition states for the cyclization reactions of C alpha-N anions derived from amides and phosphinamides

[structure: see text] Ab initio and DFT calculations indicate that the anionic cyclization of vinyl- and phenyl-carboxamides and phosphinamides metalated at the C(alpha)-N carbon fits better to a Michael-type ionic addition than to an electrocyclic ring closure. The lithium atom has no influence on the type of reaction mechanism.     

Identification of the function of gene lndM2 encoding a bifunctional oxygenase-reductase involved in the biosynthesis of the antitumor antibiotic landomycin E by Streptomyces globisporus 1912 supports the originally assigned structure for landomycinone

The angucycline antibiotic family of the landomycins displays potent antitumor activity. To elucidate early post polyketide synthase (PKS) tailoring steps of the landomycin E biosynthetic pathway in Streptomyces globisporus 1912, the mutant S. globisporus M12 was prepared through gene replacement experiment of lndM2. It encodes an enzyme with putative oxygenase and reductase domains, according to sequencing of the gene and its counterpart lanM2 from S. cyanogenus S136 landomycin A biosynthetic gene cluster. The isolation of the novel shunt products 11-hydroxytetrangomycin and 4-hydroxytetrangomycin along with the well-known angucyclines tetrangomycin and tetrangulol from the culture of S. globisporus M12 provides evidence for the involvement of lndM2 in the early biosynthetic pathway of the landomycins, in particular in the formation of the alicyclic 6-hydroxy function of the landomycin aglycon. We therefore propose LndM2 to be responsible for both hydroxylation of the 6-position and its subsequent reduction. These reactions are necessary before the glycosylation reactions can occur. The results are in agreement with the originally published structure of landomycin but do not support the recently suggested revised structure.     

Synthetic studies on lytophilippine A: synthesis of the proposed structure

Synthesis of the proposed structure of lytophilippine A was accomplished employing SmI(2)-mediated 5-exo cyclization of an aldehydo β-alkoxyvinyl sulfoxide and ring-closing metathesis reaction.     

Synthesis of indolequinones via a Sonogashira coupling/cyclization cascade reaction

A mild strategy for constructing indolequinone motifs is described on the basis of the Sonogashira reaction and a copper-catalyzed intramolecular cyclization cascade reaction. The first step involves the palladium- and copper-catalyzed reaction between halogenated naphthoquinone and terminal acetylene to generate a coupling product, which then reacts in a copper-catalyzed intramolecular cyclization with the nitrogen functional group adjacent to the carbon-carbon triple bond.     

Recyclable Hypervalent‐Iodine‐Mediated Dehydrogenative α,β′‐Bifunctionalization of β‐Keto Esters Under Metal‐Free Conditions

We have developed a method for recyclable hypervalent‐iodine‐mediated direct dehydrogenative α,β′‐ bifunctionalization of β‐ketoesters and β‐diketones under metal‐free conditions, which affords a straightforward way to synthesize benzo‐fused 2,3‐dihydrofurans. This efficient, mild method, which has a wide substrate scope and good functional‐group tolerance, was used for the multistep synthesis of the protected aglycone of a naturally occurring phenolic glycoside. A mechanism involving Michael addition to an enone intermediate and subsequent oxidative cyclization is proposed.     

Regioselective synthesis of new imidazo[4,5-e][1,3]thiazino[2,3-c][1,2,4]triazines via reaction of imidazo[4,5-e][1,2,4]triazinethiones with ethyl phenylpropiolate

A method for the regioselective synthesis of imidazo[4,5-e][1,3]thiazino[2,3-c][1,2,4]triazine derivatives has been developed by the reaction of imidazotriazinethiones with ethyl phenylpropiolate upon treatment with potassium carbonate or sodium methoxide in methanol. The synthesis was accomplished by Michael-type addition of the imidazotriazinethiones to the triple bond of ethyl phenylpropiolate followed by subsequent intramolecular cyclization.     

Stereoselective furan-iminium cation cyclization in the construction of the core structure of manzamine A

[reaction: see text] A new type of furan-iminium cation cyclization was developed and used to construct the ABC ring of manzamine A. The cyclization proceeded at the 2-position with complete regio- and stereoselectivity to give a spiro-center. The product was efficiently converted to the highly substituted core structure of manzamine A.     

A new strategy toward the total synthesis of stachyflin,a potent anti-influenza A virus agent: concise route to the tetracyclic core structure

[reaction: see text] A new strategy directed toward the total synthesis of stachyflin, a potent and novel anti-influenza A virus agent isolated from a microorganism, has been presented through the enantioselective synthesis of the tetracyclic core structure. The synthetic method features a BF(3) x Et(2)O-induced domino epoxide-opening/rearrangement/cyclization reaction as the key step.     

Microwave-assisted synthesis of new polysubstituted dienaminoesters and their cyclization to 3-bromo-2(1H)-pyridinones

A microwave-assisted, telescoped synthesis, involving a Michael-type addition followed by intramolecular cyclization, provides an effective entry to the polysubstituted 3-bromo-2(1H)-pyridinone core.     

Total synthesis of CRM646-A and -B, two fungal glucuronides with potent heparinase inhibition activities

[reaction: see text] CRM646-A (1) and -B (2), two fungal glucuronides with a dimeric 2,4-dihydroxy-6-alkylbenzoic acid (orcinol p-depside) aglycone showing significant heparinase and telomerase inhibition activities, were synthesized for the first time. The successful approach involved construction of the phenol glucuronidic linkage, via coupling of the orsellinate derivative 27 with glucuronate bromide 7, before assembly of the phenolic ester linkage in the depside aglycone. Attempts via direct glycosylation of the depside aglycone derivatives were not successful.     

Synthesis of the reported structure of crassiflorone, a naturally occurring quinone isolated from the African ebony Diospyros crassiflora, and regioisomeric pentacyclic furocoumarin naphthoquinones

A synthesis of the structure reported for the natural product crassiflorone, a furocoumarin naphthoquinone, is described. The key steps are a Diels-Alder reaction to form 2-bromo-8-hydroxy-6-methylnaphthoquinone, followed by O-protection and copper(II) mediated coupling to 4-hydroxy-5-methylcoumarin to establish the pentacyclic framework whose structure was unambiguously confirmed by X-ray crystallography. Since the spectroscopic data of the synthetic material did not match those reported for the natural product, three further regioisomeric furocoumarin naphthoquinones were prepared by copper(II) mediated coupling of 4-hydroxy-5- or 8-methyl coumarins with 5-benzyloxy-2-bromo-7-methyl- or 8-benzyloxy-2-bromo-6-methyl-1,4-naphthoquinone. Again the spectroscopic data did not match those of the natural material and therefore the true structure of crassiflorone remains unknown.     

Synthesis of cordiaquinones B, C, J, and K on the basis of a bioinspired approach and the revision of the relative stereochemistry of cordiaquinone C

Four members of the cordiaquinone family (cordiaquinones B, C, J, and K) were synthesized on the basis of a bioinspired scenario in five to six steps from trans, trans-farnesol. As key reactions we used the acid-catalyzed cyclization of a suitable epoxy terpenoid and a Diels-Alder reaction between a diene and benzoquinone. The relative stereochemistry of cordiaquinone C is opposite to that reported in the isolation paper and is in agreement with a plausible scenario for the biosynthesis of cordiaquinones from a common (E)-configurated naphthoquinone epoxide precursor. A fast and clean methodology for the synthesis of the naturally occurring (Z)-beta-farnesene from cis-nerolidol is also reported.     

Further studies of intramolecular Michael reactions of nitrosoalkenes for construction of functionalized bridged ring systems

A wide variety of stabilized carbanions have been found to participate as nucleophiles in intramolecular Michael-type conjugate additions to in situ generated nitrosoalkenes to form bridged carbocyclic systems. The vinylnitroso platforms for these cyclizations have been prepared via two key steps involving ring-closing metathesis of vinyl chlorides and regioselective conversion of vinyl chlorides to α-chloroketones with sodium hypochlorite in glacial acetic acid/acetone. An alternative approach to preparation of some cyclization substrates has involved use of more reactive enol ethers as precursors to the requisite α-chloroketones. A sulfonamide anion has also been found to be an effective nucleophile in this type of reaction, leading to formation of a 6-azabicyclo[3.2.1]octane.     

Lewis acid catalyzed rapid synthesis of 5-hydroxy-benzo[g]indole scaffolds by a modified Nenitzescu reaction

A fast solvent-less synthesis of 5-hydroxy-benzo[g]indole scaffolds is accomplished from Lewis acid-catalyzed one-pot reaction of naphthoquinone, ω-morpholinoacetophenone, and urea under microwave irradiation. The key step in the synthesis is the Michael addition followed by in situ aza cyclization reaction using urea as an environmentally benign source of ammonia.     

One-pot,four-component synthesis of benzylpyrazolyl naphthoquinone derivatives and molecular docking studies

A highly efficient, green, one-pot, four-component approach for the synthesis of benzylpyrazolyl naphthoquinone derivatives (5a–p) have been developed by the domino reaction of 2-hydroxy naphthoquinone, aromatic aldehyde, ethyl acetoacetate, and phenyl hydrazine derivatives in water and employed p-toluene sulfonic acid (p-TSA) as the right choice of catalyst at reflux. Docking simulation was performed to position compounds 5a, 5b, and 5g into the anaplastic lymphoma kinase (ALK) structure active site to determine the probable binding model.     

Synthesis,structure, and host-guest chemistry of a pair of isomeric selenanthrene-bridged molecular cages

A pair of selenanthrene-bridged molecular cages have been constructed through a one-step cyclization reaction of a tetrakis(iodo) crown ether with selenium powder. The tubular belt-shaped cage has an intrinsic cavity which can adaptively transform to accommodate electron-deficient guests forming [2]pseudorotaxane complexes. The other product was determined to be an isomeric cage featuring a Möbius strip structure, which exhibits slower twist-migration dynamics than its thianthrene counterpart. The success of using selenanthrene as joints enables an alternative way to structural design and property regulation of molecular cages.     

Studies on the syntheses of heterocyclic compounds—DXLVIII : Synthesis of a hasubanan ring system from the benzylisoquinoline reticuline

The synthesis of a cepharamine analogue (19) from reticuline (1) by phenolic oxidation is reported. Reticuline was converted into the methine base (13b), whose dihydro compound (14c) was oxidised to the seco-morphinandienone (17b). Michael-type cyclization of 17b, followed by an isomerization of the enone (18) gave the cepharamine-type compound (19).     

Synthesis of the reported structure of pogostol and a total aynthesis of (+/-)-kessane without the use of protecting groups

[reaction: see text] A short racemic synthesis of kessane from 4-hydroxy-4-methyl-2-cyclohexenone is described using a route that also resulted in the synthesis of the reported structure of pogostol. The key step involves an Fe(III)-mediated tandem radical ring-expansion/cyclization of the cyclopropylsilyl ether 9. No protecting groups are used in the entire sequence. Comparison of the NMR data of synthetic pogostol to that in the literature indicates that the structure originally proposed is incorrect.     

Cascade approach toward the core structure of neosarpagine

[reaction: see text] A palladium-catalyzed domino sequence was developed to rapidly construct the core structure of neosarpagine and other quinuclidine-related alkaloids. The cyclization of ketone 11 to ethylidene 4 with Pd(dba)2, DPEphos, LiHMDS, and ZnCl2 in THF represents a new domino process wherein a nonstabilized enolate served as a nucleophile.