Spiroketal Skeleton Research Articles

A concise approach for the synthesis of the tetracyclic framework of Lycibarbarines A and B

A simple approach for the construction of the tetracyclic spiroketal skeleton of Lycibarbarine A and B has been described. Employing a solvent free condition for epoxide opening with tetrahydroquinoline as a key reaction to couple both the fragments, an oxidation followed by TBAF-mediated silyl deprotection spiroketalization establishes the complete tetracyclic core present in these natural products.

Enantioselective Total Synthesis of (+)-Peniciketals A and B: Two Architecturally Complex Spiroketals

The enantioselective total syntheses of (+)-peniciketals A and B, two members of a family of architecturally complex spiroketals, have been achieved. Key synthetic transformations comprise Type I Anion Relay Chemistry (ARC) to construct the benzannulated [6,6]-spiroketal skeleton, a Negishi cross-coupling/olefin cross-metathesis reaction sequence to generate the trans-enone structure, and a late-stage large fragment union exploiting our recently developed photoisomerization/cyclization tactic.

A Type of Structurally Adaptable Aromatic Spiroketal Based Chiral Diphosphine Ligands in Asymmetric Catalysis.

ConspectusWhile spectacular successes have been achieved in homogeneous catalysis with the use of achiral diphosphine ligands featuring a wide natural bite angle, such as XantPhos, chiral diphosphines that can induce a large P-M-P bite angle in their transition metal complexes are conspicuously less explored in asymmetric catalysis, probably due to the challenges in the identification and efficient construction of a suitable chiral backbone. In the past decade, a highly efficient synthesis of chiral aromatic spiroketals and the corresponding diphosphine ligands (SKPs) has been developed in this group.Based on a one-pot catalytic tandem double asymmetric hydrogenation-spiroketalization ring-closure reaction sequence, these SKP ligands featuring an extraordinarily long P···P distance and a flexible backbone have been readily prepared in large scale. Remarkably versatile coordination modes have been found in the complexes of SKP with some catalysis-relevant transition metals, for example, Pd, Cu, Au, and Rh. Whereas SKP enforces an unusually large bite angle in [Pd(SKP)Cl2] and [Cu(SKP)Cl] complexes (160.1° and 132.8°, respectively), it also allows for a bimetallic Au-Au interaction (3.254 Å) in the complex of [Au2(SKP)Cl2] or a square-planar coordination geometry for the [Rh(SKP)(cod)]SbF6 complex. Such an adaptable nature of SKP ligands for transition metal coordination has profound consequences in homogeneous asymmetric catalysis, as demonstrated by their unique performance in several types of catalytic asymmetric reactions. One of the most exciting examples is SKP/Pd-catalyzed asymmetric allylic amination of Morita-Baylis-Hillman (MBH) adducts, in which SKP/Pd complexes demonstrated excellent control of regio- and enantioselectivities and exhibited exceptionally high efficiency (with a TON up to 4750) in the catalysis. SKP ligands have also found a diversity of successful applications in Cu-, Au-, or Rh-catalyzed asymmetric reactions, further attesting their wide utilities in asymmetric catalysis. Overall, this class of readily accessible SKP ligands featuring a chiral aromatic spiroketal skeleton have demonstrated unique adaptable structures in a variety of transition metal complexes and provided outstanding performance in some difficult asymmetric transformations. The works delineated herein would be expected to stimulate further research efforts on the application of this type of chiral ligand and to provide useful clues in the design of new chiral diphosphine ligands with adaptable bite angles for transition metal catalyzed asymmetric reactions.

Versispiroketal A, an unusual tetracyclic bridged spiroketal from the sponge-associated fungus Aspergillus versicolor SCSIO 41013.

Versispiroketal A (1), an unprecedented 6/5/5/6 tetracyclic polyketide featuring a rarely encountered bridge-fused spiroketal skeleton, was isolated from the sponge-associated fungus Aspergillus versicolor SCSIO 41013. The structure and absolute configuration of 1 were unequivocally determined by comprehensive spectroscopic analysis, single-crystal X-ray diffraction analysis and quantum chemical ECD calculations. Compound 1 showed weak cytotoxicity against four cancer cell lines. A plausible biosynthetic pathway for 1 was also postulated.

Spiro-Phthalides and Isocoumarins Isolated from the Marine-Sponge-Derived Fungus Setosphaeria sp. SCSIO41009.

Fourteen new polyketides classified as four phthalides, setosphalides A and B, 5- O-desmethylcolletotrialide, and ( S)-colletotrialide (1-4), three isocoumarin derivatives, exserolides I-K (5-7), four pyrones, setosphapyrones A-D (8-11), one furanone (12), and two depsidones (13 and 14), along with 17 known polyketides were isolated from cultures of the sponge-derived fungus Setosphaeria sp. SCSIO41009. The structures and absolute configurations of these new compounds (1-14) were determined by spectroscopic analyses, X-ray diffraction, chiral-phase HPLC analysis, modified Mosher's method, and comparison of ECD spectra to calculations. Setosphalides A (1) and B (2) are the first examples possessing a 5,5 spiroketal skeleton in phthalide derivatives. Botryorhodines I (13) and J (14) showed moderate antifungal activities against the phytopathogenic fungi Colletotrichum asianum and Colletotrichum acutatum. Compound 18 (7- O-demethylmonocerin) exhibited potent radical scavenging activity against DPPH.

Dimeric Octaketide Spiroketals from the Jellyfish-Derived Fungus Paecilomyces variotii J08NF-1.

Paeciloketals (1-3), new benzannulated spiroketal derivatives, were isolated from the marine fungus Paecilomyces variotii derived from the giant jellyfish Nemopilema nomurai. Compound 1 was present as a racemate and was resolved into enantiopure 1a and 1b by chiral-phase separation on a cellulose column. Compounds 2 and 3, possessing a novel benzannulated spiroketal skeleton, were rapidly interconvertible and yielded an equilibrium mixture on standing at room temperature. The relative and absolute configurations of compounds 2 and 3 were determined by NOESY analysis and ECD calculations. Compound 1 showed modest antibacterial activity against the marine pathogen Vibrio ichthyoenteri.

Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts

AbstractChiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy‐Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multipoint recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2‐position, which are prevalent in insect pheromones. Optically active (2S,5S)‐chalcogran, a pheromone of the six‐spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product.

Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts.

Chiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy-Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multipoint recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2-position, which are prevalent in insect pheromones. Optically active (2S,5S)-chalcogran, a pheromone of the six-spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product.

Total synthesis of proposed cephalosporolides H and I

An efficient total synthesis toward spiroketal diastereomers of cephalosporolides H and I was achieved, respectively, taking advantage of intramolecular Wacker-type spiroketalization on the common olefin-containing dihydroxy-γ-lactone substrate. By comparing the physical data of natural products with synthetic samples, we suggest that the reported stereochemical assignments for cephalosporolides H and I are incorrect. Our work suggests that the stereochemistry on C-6 of the core spiroketal skeleton should be revised to S from its original R assignment, and the real structures of these natural compounds should be reconsidered.

Cascade N-Alkylation/Hemiacetalization for Facile Construction of the Spiroketal Skeleton of Acortatarin Alkaloids with Therapeutic Potentiality in Diabetic Nephropathy.

Graphical The concise building of the spiroketal core of acortatarin-type alkaloids as potential therapeutic agents in diabetic nephropathy was established in four steps, through a tandem N-alkylation/hemiacetalization between pyrrole units and the corresponding halo alcohols generated by convenient halomethylation of chiral lactones from natural aldoses.The Acortatarin alkaloids exhibit a promising perspective against diabetic nephropathy and other ROS-linked diseases. Facile construction of the dioxaspirocycle motif was realized through tandem N-alkylation/hemiacetalization between pyrrole units and the corresponding halo alcohols, which were derived in turn from convenient halomethylation of chiral lactones in natural carbohydrates pool.Electronic supplementary materialThe online version of this article (doi:10.1007/s13659-014-0049-8) contains supplementary material, which is available to authorized users.

ChemInform Abstract: NH4HF2 as a Selective TBS‐Removal Reagent for the Synthesis of Highly Functionalized Spiroketal via Tandem Deprotection/Spiroketalization Procedure.

NH4HF2 has been used for the first time to selectively remove the TBS protecting groups from diol ketone precursors in the synthesis of highly functionalized spiroketals. This method allows the synthesis of [5,6], [6,6], and [6,7] spiroketal skeletons, as well as benzannulated spiroketal with retention of acid-sensitive groups. In this way, spiroketals can be synthesized with diverse substituent groups in the skeleton or on side chains. To demonstrate the utility of this methodology, the diverse transformations of highly functionalized spiroketal 3f were also investigated.

NH4HF2 as a Selective TBS-Removal Reagent for the Synthesis of Highly Functionalized Spiroketal via Tandem Deprotection/Spiroketalization Procedure

NH4HF2 has been used for the first time to selectively remove the TBS protecting groups from diol ketone precursors in the synthesis of highly functionalized spiroketals. This method allows the synthesis of [5,6], [6,6], and [6,7] spiroketal skeletons, as well as benzannulated spiroketal with retention of acid-sensitive groups. In this way, spiroketals can be synthesized with diverse substituent groups in the skeleton or on side chains. To demonstrate the utility of this methodology, the diverse transformations of highly functionalized spiroketal 3f were also investigated.

Spiroketals of Pestalotiopsis fici Provide Evidence for a Biosynthetic Hypothesis Involving Diversified Diels–Alder Reaction Cascades

Chloropestolides B-G (1-6), six new metabolites featuring the chlorinated spiro[benzo[d][1,3]dioxine-2,7'-bicyclo[2.2.2]octane]-4,8'-dione (1-3) and spiro[benzo[d][1,3]dioxine-2,1'-naphthalene]-2',4-dione (4-6) skeletons, and their putative biosynthetic precursor dechloromaldoxin (7) were isolated from the scale-up fermentation cultures of the plant endophytic fungus Pestalotiopsis fici . The structures of 1-7 were determined mainly by NMR experiments. The absolute configurations of 1-3 were deduced by analogy to the previously isolated metabolites from the same fungus (9 and 13-18), whereas those of 4, 5, and 7 were assigned by electronic circular dichroism (ECD) calculations. Structurally, the spiroketal skeletons found in 1-3 and 4-6 could be derived from 2,6-dihydroxy-4-methylbenzoic acid with chlorinated bicyclo[2.2.2]oct-2-en-5-one and 4a,5,8,8a-tetrahydronaphthalen-2(1H)-one, respectively. Biogenetically, compounds 1-6 were derived from the same Diels-Alder precursors as the previously isolated 9 and 12-18. In addition, compounds 2 and 3 were proposed as the biosynthetic intermediates of 17 and 16, respectively. Compound 1 was cytotoxic to three human tumor cell lines.

Nickel‐Mediated Inter‐ and Intramolecular Reductive Cross‐Coupling of Unactivated Alkyl Bromides and Aryl Iodides at Room Temperature

A nickel-mediated intermolecular reductive cross-coupling reaction of unactivated alkyl bromides and aryl iodides at room temperature has been developed and successfully extended to less explored intramolecular versions and tandem cyclization-intermolecular cross-coupling. Highly stereoselective (or stereospecific) synthesis of linear-fused perhydrofuro[2,3-b]furan (pyran) and spiroketal skeletons allows rapid access to these useful building blocks, which would be potentially valuable in the synthesis of relevant natural products. A rational explanation for the formation of contiguous stereogenic centers is given.

Chloropupukeanolides C–E: Cytotoxic Pupukeanane Chlorides with a Spiroketal Skeleton from Pestalotiopsis fici

Chloropupukeanolides C-E (8-10), three highly functionalized secondary metabolites featuring a novel spiroketal skeleton derived from the chlorinated tricyclo-[4.3.1.0(3, 7)]-decane (pupukeanane) and the 2,6-dihydroxy-4-methylbenzoic acid moieties, were isolated from the scale-up fermentation extract of the plant endophytic fungus Pestalotiopsis fici. The constitutions of compounds 8-10 were elucidated primarily by NMR experiments. Their relative configurations were deduced by analogy to metabolites 4-6, which were previously isolated from the same fungus. The absolute configuration of 8 was assigned by X-ray crystallography and those of 9 and 10 by quantum-chemical CD calculations. Biogenetically, chloropupukeanolides C-E (8-10) are presumably derived from the same oxidation-induced Diels-Alder reaction pathway as compounds 1 and 4-7, via the putative biosynthetic precursors 2 and 3. The opposite configurations of the complete "Southern parts" of 8 and 9 suggests that this Diels-Alder reaction is stereochemically not very selective. Compounds 8-10 showed significant cytotoxicity against a small panel of human tumor cell lines and weak activities against the pathogens of tropical diseases.

An Efficient Synthesis of Highly Functionalized [5,6] Aromatic Spiroketals by Hetero-Diels−Alder Reaction

A hetero-Diels-Alder reaction of vinyl sulfoxides with o-quinone methides precursor constructs highly functionalized [5,6] aromatic spiroketal skeletons in moderate to good yields with high regioselectivity. The two functional groups (ketone and olefin) can be further subjected to many synthetic transformations.

Total Synthesis of (±)‐γ‐Rubromycin on the Basis of Two Aromatic Pummerer‐Type Reactions

Double or nothing: In a convergent synthesis of the title compound, a potent inhibitor of human telomerase, two different aromatic Pummerer-type reactions were employed to construct the pivotal bisbenzannelated spiroketal skeleton from the two fragments shown in the scheme. This methodology offers convenient access to a wide range of substituted bisbenzannelated spiroketals from naphthol derivatives. MOM=methoxymethyl.

Expeditious Synthesis of the Aromatic Spiroketal Skeleton Using Hetero‐Diels—Alder Cycloaddition.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Expeditious synthesis of the aromatic spiroketal skeleton using hetero-Diels–Alder cycloaddition

The hetero-Diels–Alder reactions of enolic ethers generated from methylenation of various esters are described, which allow for the rapid synthesis of various substituted [6,6] aromatic spiroketal skeletons.

A facile synthesis of fused spiroketal skeleton: 2,2′-spirobi(4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydrochroman)

A one-pot synthesis of fused spiroketal skeleton, 2,2′-spirobi(4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydrochroman) 4a– c , has been achieved for the first time by an application of Michael reaction between dimedone (5,5-dimethylcyclohexan-1,3-dione) 1 and trans, trans-diarylideneacetone (1,5-diaryl-1,4-pentadien-3-one) 2 using anhydrous ZnCl 2 as catalyst. The spiroketalization was achieved efficiently via intramolecular cyclization of the Michael 1:2 adduct.