Concise synthesis of the oxapentacyclic core of cortistatin A

A concise synthetic approach for constructing the oxapentacyclic framework of cortistatin A is described. The synthesis features a furan-oxyallyl [4 + 3] cycloaddition and double-intramolecular aldol reactions. In addition, an interesting core structure was obtained in 11 steps from furan by using our method.     

Synthesis and stereochemistry of novel [1,2,4]oxadiazolo[4,5-a][1,5]benzodiazepine derivatives

An one-pot synthetic approach to the novel 3a,4,5,6-tetrahydro[1,2,4]oxadiazolo[4,5-a][1,5]benzodiazepine system, by 1,3-dipolar cycloaddition of benzonitriloxides to 1,5-benzodiazepine derivatives, is described. The structure and stereochemistry of the obtained adducts have been assigned by means of spectroscopic measurements.     

Gold(I)‐Catalyzed 1,2‐Acyloxy Migration/[3+2] Cycloaddition of 1,6‐Diynes with an Ynamide Propargyl Ester Moiety: Highly Efficient Synthesis of Functionalized Cyclopenta[b]indoles

A gold‐catalyzed cycloisomerization of 1,6‐diynes containing an ynamide propargyl ester or carbonate moiety has been developed that provides an attractive route to a diverse‐substituted 3‐acyloxy‐1,4‐dihydrocyclopenta[b]indoles. Mechanistic studies indicate that the reaction likely proceeds through a competitive 1,2‐OAc migration followed by [3+2] cycloaddition of the vinyl gold–carbenoid intermediate with the pendant triple bond. The synthetic utility of the obtained cyclopenta[b]indole products was demonstrated by their efficient transformations by deprotection or double‐bond isomerization reactions.     

Unprecedented influence of remote substituents on reactivity and stereoselectivity in Cu(I)-catalysed [2 + 2] photocycloaddition. An approach towards the synthesis of tricycloclavulone

Cu(I)-catalysed [2 + 2] photocycloaddition of 1,6-dienes embedded in a furano sugar is described in connection to a synthetic approach to an abnormal marine prostanoid tricycloclavulone. An unprecedented influence of remote substituents on the reactivity and stereoselectivity of the photocycloaddition reaction has been uncovered during this investigation. While an alkene substituent inhibits cycloaddition through steric effects, a substituent having a hydroxyl or alkoxy group at the same location facilitates cycloaddition exclusively from its own side. This investigation has led to the synthesis of a functionalised 5,4-fused core unit of tricycloclavulone.     

Understanding the puzzling chemistry of bicyclo[2.1.0]pentane

Three thermal reactions of bicyclo[2.1.0]pentane have been studied by CASPT2-g3 and CASSCF electronic structure calculations. They are isomerization to cyclopentene, isomerization to 1,4-pentadiene, and cycloaddition to fumaronitrile. All three of these reactions exhibit unusual features that have prompted mechanistic debate. The present computational results provide a basis for understanding the experimental observations.     

Synthesis of the Bicyclic Lactone Core of Leonuketal,Enabled by a Telescoped Diels–Alder Reaction Sequence

The Diels–Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products; however, successful application of the intermolecular Diels–Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]‐bicyclic lactone ring system and its [3.2.1] isomer. Our four‐step, protecting‐group‐free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels–Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product.     

An IMDAF cycloaddition approach toward the synthesis of the lycopodium alkaloid (±)-fawcettidine

Using an intramolecular [4 + 2] cycloaddition/rearrangement cascade of 3-(1,4-dioxaspiro[4.4]non-7-en-7-yl)-N-furan-2-ylpropionamide (23) as the key step, the BCD core of the lycopodium alkaloid fawcettidine was constructed. Heating the initially formed Diels-Alder cycloadduct at 180 °C results in a nitrogen-assisted ring opening followed by a deprotonation/reprotonation of the ensuing zwitterion to give a rearranged hexahydroindolinone. Our attempts to induce a related intramolecular furan Diels-Alder reaction (IMDAF) from the corresponding ketone of 23 failed to give any cycloaddition product. Instead, the only product obtained corresponded to a cyclopentenone derivative derived by isomerization of the double bond into the thermodynamically more stable α,β-position. Efforts toward construction of the final skeleton of fawcettidine by ring A closure of the rearranged cycloadduct derived from furanyl amide 23 are discussed.     

Quantum mechanical inspection of the Diels-Alder approach to biaryls mechanism

The Diels-Alder reaction of substituted cyclohexadienes with substituted phenylacetylenes offers an attractive alternative for the synthesis of biaryl compounds via a two-step cycloaddition/cycloelimination pathway. Quantum mechanical calculations using B3LYP and M06-2X density functional methods for the reaction of 2-chloro-6-nitrophenylacetylene with 1-carbomethoxy-cyclohexadiene show the reaction proceeds by a stepwise diradical [4+2] cycloaddition followed by concerted [2+4] cycloelimination of ethylene. [2+2] cycloadducts are also the result of stepwise addition. [2+2] cycloadducts isomerize to [4+2] cycloadducts via diradical pathways, which involve the same diradical intermediate in cycloaddition. There is also a competitive conrotatory ring opening followed by trans-cis double bond isomerization pathway of the [4.2.0] bicycle (the [2+2] cycloadduct) to give the cis,cis,cis-1,3,5-cyclooctatriene.     

Precipiton reagents: precipiton phosphines for solution-phase reductions

[structure: see text] [structure: see text] [structure: see text] Several Precipiton phosphines were prepared and employed in the Staudinger reaction and in the reduction of secondary ozonides. Both amines and aldehdyes were obtained in good to excellent yields and purities. After use of the phosphine, isomerization and precipitation of the spent phosphorus reagent were induced by exposure to visible light in the presence of erythrosin B, a triplet sensitizer. Products were isolated by simple filtration. The use of the triplet sensitizer has the added advantage of eliminating [2 + 2] cycloaddition reactions between trans-Precipitons.     

1-Oxo-5-hydroxytryptamine: a surprisingly potent agonist of the 5-HT3 (serotonin) receptor

A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds via the [3+2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization. This molecule proves to be a competent agonist (equipotent to serotonin) of the 5-HT3 receptor, demonstrating that the indolic proton of serotonin is not essential to its activation of the receptor.     

Synthetic studies toward the pyran core and the amide side chain of psymberin

A synthetic approach to the polysubstituted pyran core and amide side chain of psymberin (irciniastatin A) using stereoselective organoboron methodology is described. An advanced oxyranyl pyran intermediate was prepared using a catalytic enantioselective and diastereoselective three-component reaction involving first an inverse electron-demand hetero [4+2] cycloaddition between 3-boronoacrolein pinacolate and 1-ethoxy-2-methylpropene, followed by an allylboration of ethyl glyoxylate. The amide side chain was prepared highly efficiently using the first example of a doubly diastereoselective allylboration of a chiral α-alkoxy aldehyde under the Lewis acid-catalyzed reaction manifold.     

Total Synthesis of (±)‐Phomoidride D

Described herein is a synthetic strategy for the total synthesis of (±)‐phomoidride D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular Diels–Alder cycloaddition. A subsequent SmI₂‐mediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion.     

Asymmetric synthesis of the spirocyclic core of the cylindricine-type alkaloids

Marine alkaloids from the cylindricine and lepadiformine families possess an interesting spirotricyclic skeleton. An intramolecular nitrone/olefin 1,3-dipolar cycloaddition has been used to form their spirocyclic 1-azaspiro[4.5]decane core in a regio- and stereoselective fashion. The cyclization precursor can be easily accessed using the asymmetric electrophilic hydroxyamination of enolate.     

Total Synthesis of Maoecrystal P: Application of a Strained Bicyclic Synthon

A new strategy was devised for the total synthesis of highly oxidized ent‐kauranoids. A highly regio‐ and diastereoselective intermolecular Diels–Alder cycloaddition involving a diene embedded in a substituted bicyclo[4.1.0] skeleton was used to assemble all carbon centers but C17 of the target molecule at an early stage of the synthesis. Subsequent synthetic steps, including redox manipulations, SmI₂‐mediated cyclization, and isomerization reactions, afforded the antitumor natural product maoecrystal P.     

Non-metathesis reactions of ruthenium carbene catalysts and their application to the synthesis of nitrogen-containing heterocycles

Non-metathesis reactions of ruthenium carbene catalysts, such as olefin isomerization, hydrogenation, radical reaction, activation of silane, cyclopropanation, epimerization cocyclopropane, [3 + 2] cycloaddition, and cycloisomerization, are summarized. The utility of these reactions was demonstrated by the synthesis of indole using olefin isomerization and subsequent ring-closing metathesis, the synthesis of indoline using cycloisomerization, and the synthesis of the putative structure of fistulosin using cycloisomerization as a key step.     

Total Syntheses of Sarcandrolide J and Shizukaol D: Lindenane Sesquiterpenoid [4+2] Dimers

The syntheses of members of a family of lindenane sesquiterpenoid [4+2] dimers led to the total syntheses of sarcandrolide J and shizukaol D. Inspired by a modified biosynthetic pathway, a cascade featuring furan formation/alkene isomerization/Diels–Alder cycloaddition was devised to construct the congested polycyclic architecture of the target molecules with the correct stereochemistry. This study presents a pioneering synthetic entry to this family of natural products and paves the way for fully exploring their biological functions.     

An efficient approach to azirino and pyrrolo-fused dibenzazepines. Conformations of substituted dibenzo[c,f]pyrrolo[1,2-a]azepines

An effective approach to azepino-fused heterocycles is described. trans-1-Aryl-7,11b-dihydro-1H-azirino[1,2-a]dibenzo[c,f]azepines were synthesised via a domino sequence: isomerization of gem-dichloroaziridine-intramolecular Friedel-Crafts acylation of the tethered benzene ring catalysed by SnCl(4) and subsequent hydride induced intramolecular cyclization. Cycloaddition of dibenzazepinium ylides, generated by heating these aziridines, to activated C[double bond]C, C[triple bond]C dipolarophiles and fullerene C(60), leads to derivatives of dibenzo[c,f]pyrrolo[1,2-a]azepine. The reaction proceeds with complete stereoselectivity via cycloaddition of only W-ylide, which due to the high barrier does not undergo E,Z-isomerization under the reaction conditions. It was found that 2,3,9,13b-tetrahydro-1H-dibenzo[c,f]pyrrolo[1,2-a]azepine systems can exist in conformations of two types depending on the substituents at the pyrrolidine carbons in β-position with respect to nitrogen. Details of cycloaddition reactions and the conformational behavior of cycloadducts were studied by DFT calculations at the B3LYP/6-31G(d) level.     

Efficient synthetic access to the hetisine C20-diterpenoid alkaloids. A concise synthesis of nominine via oxidoisoquinolinium-1,3-dipolar and dienamine-Diels-Alder cycloadditions

A concise synthetic approach to the hetisine C20-diterpenoid alkaloids is reported. The total synthesis of (+/-)-nominine was accomplished in a 15-step sequence employing a dual cycloaddition strategy. Key features of the synthesis include a reversible intramolecular 4-oxidoisoquinolinium betaine dipolar cycloaddition in conjunction with a pyrrolidine-induced dienamine isomerization/Diels-Alder cascade.     

Diastereoselective Synthesis of Cyclopentanoids: Applications to the Construction of the ABCD Tetracyclic Core of Retigeranic Acid A

A concise and efficient approach for the construction of the tetracyclic carbon skeleton of retigeranic acid A is described. The key transformations include a novel Rh‐catalyzed [3+2] cycloaddition of enyol to afford cyclopentanoid E , bearing two contiguous quaternary stereocenters at the bridgehead positions, and an intramolecular Pauson–Khand reaction to construct the advanced tetracyclic core structure of retigeranic acid A.     

Linear encoding of functional groups in the synthesis of heterocyclic compounds: cycloaddition of enyne and alkyne units

A family of novel [4 + 2] cycloaddition reactions is discussed for the efficient preparation of poly-substituted heterocyclic compounds in a single step starting with linear precursors. The high selectivity of the intramolecular transformation and the predefined position of the substituents in the product were governed by linear encoding in the structure of the starting reagents. The designed reactions utilized the green chemistry potential of the cycloaddition approach and provided a convenient synthetic route to cyclopentapyridines, indoles, isoindoles, indolizines, isophosphindoles, benzofurans, benzothiophenes, and benzoselenophenes (and corresponding dihydro derivatives).