Cycloaddition reactions 0-carbolines

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Danishefsky has used the imine-diene cycloaddition reaction (Scheme 3) (85TL5983). Reaction of Hagemann s ester 18 with dihydro-)3-carboline 14 in chloroform without catalyst afforded 50% of the pentacyclic lactam 19. Reduction of 19 with lithium aluminum hydride followed by acidic hydrolysis gave the known yohimbine derivative 20. 

Indole has also been used as a dienophile in cycloaddition reactions with 1,2,4-triazines.414 Depending on the substituents bound to the heterocyclic system / - or y-carbolines (33-89% or 6-22% yield, respectively), benzo[/][l,7]naphthyridines (2-50%) or 5-(indol-3-yl)-l,2,4-tri-azines are isolated (60-64%). 

The initial success of the inverse electron demand [4 + 2]cycloaddition reaction of electron deficient, 1,2,4-triazine (61) with a-aryl enamine (60) to formulate the 4-arylpyridine forms the basis of a complementary approach to the CDE ring system of lavendamycin. In this strategy the oxidative insertion of aryl halide bond to provide the p-carboline derivative in the presence of palladium (0) was the notable feature. In a recently published article by Boger, a total synthesis of lavendamycin starting from the precursor 63 has been presented. The utility of... 

Originally, the pyridine construction reaction was based on cobalt catalysis and restricted to the use of acetonitrile or alkyl nitriles as one of the cycloaddition partners. However, recent advancements in this area have led to the development of certain ruthenium or rhodium catalysts, allowing the use of methylcyanoformate as an electron-deficient nitrile component in crossed [2 - - 2 - - 2]-cycloaddition reactions [39]. From the point of view of applications, the use of methylcyanoformate in transition-metal-catalyzed pyridine formation reaction is quite beneficial because the ester moiety might serve as a functional group for further manipulations. It might also serve as a protective group of the cyanide moiety, because cyanide itself cannot be used in this reaction. These considerations led to the design of a quite flexible approach to substituted 3-(130)- and y-carbolines (131) based on transition-metal-catalyzed [2 -f 2 -I- 2] cycloaddition reactions between functionalized yne-ynamides (129) and methylcyanoformate (Scheme 7.28) [40]. 

Snyder and coworkers followed a completely different path to canthin-6-one (Fig. 23). Earlier they had shown that indole-substituted 1,24-triazine 66 could be heated in refluxing triisopropylbenzene (bp = 232 °C) to give /3-carboline 67 via an intramolecular cycloaddition/cycloreversion reaction [58]. Selective oxidation of 67 at C-6 was achieved through the use of triethylbenzylammonium permanganate [59]. Success of the reaction proved to be very sensitive to the solvent chosen. Heating 67 for 4 h at 70 °C in a 5 1 mixture of dichloromethane and acetic acid gave a 65% yield of 63, yet use of increasing amounts of dichloromethane slowed the reaction down (no reaction occurred in pure dichloromethane), while use of pure acetic acid led to an intractable mixture. 

Manzamine alkaloids can be isolated from marine sponges. They often contain /3-carboline. This group has a diverse range of bioactivities. It also has its own way of establishing its structures. An intramolecular Diels-Adler reaction for manzamines has been proposed. The a is bisdihydropyridine (derived probably from amonia), and the (3 is intramolecular cycloaddition in a pentacyclic... 

Imino Diels-Alder reactions.1 The cycloaddition of dihydro-p-carbolines with... 

It has been demonstrated that N-hydroxytryptophan can be converted to /3-carbolines in two ways (Fig. 41). Pictet-Spengler reaction of 1 with acetals provided the N -hydroxytetrahydro-/8-carbolines (2) (287). A modified Bischler-Napieralski reaction of 1 with trimethylorthoformate gave N -0X0-3,4-dihydro-/3-carbolines (3), the nitrone function of which can undergo 1,3-dipolar cycloaddition with alkenes (288) and nitriles (289), providing isoxazolidine (4) and dehydro-1,2,4-oxadiazoline (5), annulated TBCs, respectively. Nitrone 3 also was obtained by oxidation of the N-hydroxy-j8-carboline 2 with 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (DDQ). N-Oxygenated TBCs showed no affinity for the benzodiazepine and tryptamine receptors (290). Unfortunately, no toxicity data were recorded for these substituted hydroxylamines. 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

Danishefsky reported some years ago that acyclic, unactlvated imines undergo Lewis acid catalysed cycloaddition with siloxydienes to give six-membered nitrogen heterocycles. Two reports have now extended these observations to include the reaction of cyclic imines with dienes. Danishefsky s group has also described the cycloaddition of dihydro-B-carbolines with three siloxydienes to... 

---