Isatogenols as Precursors for the Synthesis of Fully Substituted Indolines through Regio- and Stereoselective [3 + 2] Cycloaddition Using Various Olefins.

Here, we describe a unique reactivity of isatogen derivatives bearing a hydroxy group at the C3-position (isatogenol) and their synthetic application to highly regio- and stereoselective [3 + 2] cycloaddition reactions. This method provides facile access to polyfused and highly functionalized heterocycles including consecutive stereocenters. Furthermore, DFT calculations revealed that hydrogen bonding is a key to controlling the regio- and stereoselectivity in the cycloaddition using acrylates.

Nickel-catalysed regio- and stereoselective hydrocyanation of alkynoates and its mechanistic insights proposed by DFT calculations.

We have developed a nickel-catalysed regio- and stereoselective hydrocyanation of alkynoates that gives syn-ß-cyanoalkenes. DFT calculations suggest that a favored transition state promotes Cα-H bond formation for determining regio- and stereoselectivity of the products.

Megalourethra and bladder foreign body in a female patient.

Key Clinical Message: Undiagnosed female megalourethra can be a cause of iatrogenic bladder foreign body. Abstract: Foreign bodies in the urinary bladder are relatively rare. Female megalourethra is an extremely rare congenital disorder which is usually associated with Müllerian anomalies. We describe a case of an iatrogenic bladder foreign body and a megalourethra in a young woman with normal gynecological organs.

Regio-divergent nickel catalysis: intramolecular [4+2] and [2+2] cycloaddition reactions between vinylallenes and alkynes.

Vinylallenes have been recognized as versatile C2 and C4 components for nickel-catalyzed intramolecular [4+2] and [2+2] cycloadditions. The former reaction was promoted by a Ni(0) complex (up to quantitative yield), and a Ni(II) salt was a key species for the latter reaction to give the corresponding regio- and stereocontrolled cycloadducts (up to 88% yield). DFT studies revealed that both reaction pathways involve a concerted mechanism through the activation of different C-C multiple bonds in the substrates.

Nickel-Catalyzed Hydrocyanation of Allenes and Its Application.

Cyano (CN) groups are equivalent to carbonyl as well as amino- and hydroxymethyl groups. Therefore, their catalytic introduction under metal catalysis is an important issue in synthetic organic chemistry. Ni-catalyzed hydrocyanation is one of the most well-investigated, powerful tools for installing a CN group. However, it is still difficult to control chemo- and regioselectivity. In this review, the author uses allenes to enable regio-, stereo-, and face-selective transformations to natural product synthesis and axial chirality transfer.

Cobalt-catalyzed cyclization with the introduction of cyano, acyl and aminoalkyl groups.

An efficient synthesis of carbo- and heterocycles using C[double bond, length as m-dash]C, C[double bond, length as m-dash]O and C[double bond, length as m-dash]N bonds under cobalt catalysis is described. The substituents on olefins are key for controlling the regio- and chemoselectivity in the initial hydrogen atom transfer step and quaternary carbons are efficiently constructed under mild conditions. Cyclopropane cleavage and tandem cyclization give highly functionalized bicyclic skeletons in a single operation.

Total Synthesis of Lundurine and Related Alkaloids: Synthetic Approaches and Strategies.

This review focuses on the total synthesis of lundurines A-C. Their main structural feature is a unique cyclopropa[b]indole core that has been found only in these alkaloids. In addition to this characteristic structure, the biological activity makes them as attractive synthetic targets. However, almost two decades passed from their isolation and structural determination in 1995 to their first total synthesis. The first part of this review summarizes the synthetic approaches to the tri- and tetracyclic ring systems of lundurine as well as an inter- and intramolecular cyclopropanation strategy that gives the cyclopropa[b]indole core. The second part presents a detailed description of four total syntheses that were reported from 2014 to 2016. In addition, the asymmetric total synthesis of the related alkaloids grandilodine C and lapidilectine B is described.

Transfer of axial chirality through the nickel-catalysed hydrocyanation of chiral allenes.

The transfer of axial chirality of allenes is beginning to be exploited as a powerful method for creating central chirality, particularly through the use of transition metal catalysis. In this communication, the transfer of axial chirality of chiral allenes via nickel-catalysed hydrocyanation is achieved through both regio- and face-selective hydronickelation as well as regioselective reductive elimination. This protocol was applied to 12 substrates and gave chiral carbonitriles with up to 97% ee. Further application to hydrocyanative cyclization using a chiral allene-yne is also presented, along with a discussion of the corresponding mechanism of racemization.

Total Syntheses of (+)-Grandilodine†C and (+)-Lapidilectine†B and Determination of their Absolute Stereochemistry.

Enantioselective total syntheses of the Kopsia alkaloids (+)-grandilodine C and (+)-lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)-grandilodine C was achieved by palladium-catalyzed intramolecular allylic amination and ring-closing metathesis to give 8- and 5-membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)-lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies.

A new protocol for nickel-catalysed regio- and stereoselective hydrocyanation of allenes.

Regio- and stereoselective hydrocyanation under nickel catalysis is described. This report shows that allenyl C-C double bonds are discriminated and converted to the corresponding carbonitriles as a single product. The key functionalities for achieving high regio- and stereocontrol are aryl and cyclopropyl groups in the substrates.

Asymmetric total synthesis of (-)-lundurine B and determination of its absolute stereochemistry.

A total synthesis of the Kopsia tenuis alkaloid (-)-lundurine B has been achieved. A quaternary chiral carbon has been created by an asymmetric deprotonation using a symmetric spiro cyclohexanone intermediate with a chiral lithium amide. The hexacyclic skeleton was sequentially constructed through metal-mediated reactions. The absolute stereochemistry of intermediate 5 has been unambiguously established by X-ray crystallographic analysis. This is the first description of the absolute stereochemistry of Kopsia tenuis alkaloids based on chemical synthesis.

A concise and versatile synthesis of alkaloids from Kopsia tenuis: total synthesis of (±)-lundurine A and B.

A total synthesis of (±)-lundurines A and B is described. These natural products have a unique hexacyclic skeleton which includes a cyclopropane-fused indoline. A stereospecific construction of the pentasubstituted cyclopropane core was achieved, by radical cyclization using SmI2, with perfect stereoselectivity. Cyclizations to give seven- and five-membered heterocycles, under palladium and ruthenium catalysis, respectively, accomplished the total syntheses. The late-stage construction of the F ring by ring-closing metathesis enabled access to the title compounds from a spiroindoline intermediate which is a common structure of other kopsia alkaloids.

Total synthesis of (±)-lundurine B.

A total synthesis of (±)-lundurine B was accomplished. A combination of stereoselective intramolecular cyclopropane formation and aryl amination furnished cyclopropane-fused indoline stereoselectively. Ring-closing metathesis (RCM) of siloxy diene and intramolecular aminoacetal formation followed by bridgehead vinylation of an anti-Bredt iminium cation led to the construction of six- and seven-membered rings with a quaternary carbon center. After the formation of dihydropyrrole by RCM, the Boc-protecting group of indoline was converted into the corresponding methyl carbamate via silyl carbamate to complete the total synthesis of (±)-lundurine B. The characteristic rearrangement of the cyclopropane-fused indoline skeleton is also described.

Total synthesis of schizocommunin and revision of its structure.

A proposed structure for schizocommunin (Z)-1(hydroxy) and its geometric isomer (E)-1(hydroxy), which exist in a keto form, has been synthesized. However, the spectroscopic data of (Z)-1(keto) and (E)-1(keto) were not consistent with those reported for natural schizocommunin. After reinvestigating the spectral data for natural schizocommunin, we synthesized the quinazolinone derivative (Z)-2 as a revised structure for schizocommunin. All of the spectral data of (Z)-2 were completely identical to those reported for natural schizocommunin. (Z)-2 showed moderate antiproliferative activity.

Regioselective hydronickelation of allenes and its application to the hydrocyanative carbocyclization reaction of allene-ynes and bis-allenes.

The carbocyanative cyclization of allene-ynes and bis-allenes under nickel catalysis is described. The key steps are the regioselective hydronickelation of allenes and subsequent cyclization via carbometalation. The former step determines the reaction pathway, and the latter controls the stereochemistry of substituted olefins. The products are useful carbo- and heterocycles that include a cyano group, functionalized double bonds, and quaternary carbons.

Endoscopic mucosal resection with circumferential mucosal incision of duodenal carcinoid tumors.

Duodenal carcinoids are a rare form of neuroendocrine tumors, and tend to invade the submucosa during the early stage. Endoscopic treatment is generally recommended for duodenal carcinoids less than 10 mm in diameter. Although a few reports have described the use of endoscopic resection of duodenal carcinoids, there are no published studies on endoscopic mucosal resection with circumferential mucosal incision (EMR-CMI). We performed EMR-CMI for 5 cases of duodenal carcinoids in the duodenal bulb. The mean tumor diameter was 4.6 ± 1.8 mm. Although all of the tumors were located in the submucosa, R0 resection was performed without complication in each case. EMR-CMI may thus be a safe and effective treatment for duodenal carcinoids less than 10 mm in diameter.

Anti carbocyanative cyclization of enynes under nickel catalysis.

Anti carbocyanative cyclization using 1,6-enynes under nickel catalysis is described. This reaction is triggered by hydronickelation to alkenes followed by carbometalation. Steric repulsion caused by the bulky substituents on alkynes promotes isomerization of the carbon-carbon double bond geometry in an organonickel intermediate to introduce both alkyl and cyano groups in an anti fashion.

Catalytic dicyanative [4 + 2] cycloaddition triggered by cyanopalladation using ene-enynes and cyclic enynes with methyl acrylate.

Palladium-catalyzed dicyanative [4 + 2] cycloaddition using various ene-enynes was investigated. The key species in this process is a cyanoallene intermediate that is obtained by the cyanopalladation of conjugated enynes followed by 5-exo-cyclization. To achieve an efficient [4 + 2] cycloaddition reaction, both the smooth generation of this species and critical control of regioselectivity in the 6-endo-cyclization step are quite important. A study of the substrate scope revealed that the reaction is strongly affected by the steric bulk of the substituents on the enyne and alkene units and prefers to give trans-fused cycloadducts. The stereochemistry of olefins was reasonably transferred to the corresponding products. Further study proved that this transformation includes not a thermal [4 + 2] cycloaddition process via 1,2-dicyanoalkenes generated in situ but rather a palladium-mediated stepwise cyclization sequence to control a maximum of five contiguous stereogenic centers in a single operation. An intermolecular version using methyl acrylate with conjugated cyclic enynes and TMSCN also gave the corresponding [4 + 2] cycloadducts in a regioselective manner.