Bischler-Napieralski ring groups

An improved synthesis of polyhydroxybenzylisoquinolines without protection of the hydroxy-groups has been reported, in which Bischler-Napieralsky ring closure of the appropriate amide is achieved with phosphorus oxychloride in acetonitrile coclaurine, isococlaurine, and reticuline, as well as a key intermediate in the synthesis of multifloramine, have been prepared in this way. 

Bischler-Napieralski ring closure with cycloalkane methylene groups... 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

Reduction of the imine with sodium borohydride leads to an intermediate amino-ester that cyclizes spontaneously to the <5-lactam function. Solvolysis of the acetyl group with methoxide followed by acylation of the hydroxyl group thus liberated with trimethoxybenzoyl chloride leads to 38. Bischler-Napieralski cyclodehydration (phosphorus oxychloride) effects closure of the remaining ring. Reduction of the imine thus formed with sodium borohydride gives 39. This, it should be noted, leads to the... 

The synthesis continued with the formation of the 2-azabicyclo[3.3.1]nonane ring (D, E-rings), and epimerization of the cyano group at C-20 to an axial position. Closure of the C ring using a Bischler-Napieralski cyclization gave the quaternary indole alkaloid, ( )-melinonine-E (159). A closely related analog, ( )-strychnoxanthine, was also synthesized by a similar method [67]. 

A suitably positioned acylamino group is annulated to a ring-carbon in a Bischler-Napieralski reaction with phosphorus oxychloride comparison of a number of reagents (phosphorus pentoxide-toluene, phosphorus pentoxide-tetralin, phosphorm oxychloride, PPA) for their efficacy in this reaction showed that PPA was the most useful. 

There are two problems to be solved in perfecting the benzylisoquinoline approach synthesis of 7,8-substituted benzylisoquinolines with appropriate functional groups and formation of the oxepine ring. Bischler-Napieralsky cyclization of amides (66) is known to afford 6,7-substituted benzylisoquinolines. To avoid this unwanted reaction, two new approaches have been developed, namely, activating position C-2 and blocking position C-6. 

The structural dissection of the lavendamycin molecule 40 revealed a quinolinequinone (AB) and p-carboline (CDE) framework. Both these units are historically known and numerous methodologies for them have been formulated. It was therefore, hoped that the synthetic efforts towards 40 would not pose much difficulties. The synthetic tactics towards 40 revolve around the Bischler-Napieralski reaction between p-methyltryptophan and quinaldic acid to construct ring C, and in the process, bridging the two subunits. However, Roger s group preferred to extend the inverse electron demand Diels-Alder reaction, successfully demonstrated for streptonigrin, to the synthesis of lavendamycin. 

As it would be expected, the Bischler-Napieralski reaction as an intramolecular electrophilic substitution reaction is accelerated in the presence of an electron-donating group on the aromatic ring. With respect to that, electronic effects influence the regioselectivity of the reaction, leading the substitution typically to the carbon bearing the higher electron density. On the other hand, substitution on the phenylethyl side chain is usually well tolerated." ... 

The route commenced with the condensation of amine 229 and carboxylic acid 230 at 200 °C. Subsequent Bischler-Napieralski reaction and sodium borohydride reduction established the C/D ring system of morphine and delivered tetrahydroisoquinoline 231 in good yield. Next, Birch reduction and Af-formylation afforded enol ether 232, which was converted into the corresponding ketal before reaction with bromine allowed the isolation of the cyclization precursor. The halide in 233 serves to protect the para position in the aromatic ring in the subsequent acid-mediated electrophilic cyclization reaction—a common strategy that has also been applied by other research groups in their endeavors toward morphine and related alkaloids. 

In the initial applications of Diels-Alder chemistry to yohimbine alkaloid synthesis, the Kametani (24-27) and Takano (28) groups have both examined reactions between furan derivatives and maleic anhydride. In the initial investigations of Kametani and his coworkers (24) (Scheme 3.10), the Diels-Alder adduct (57) of furan and maleic anhydride underwent bromolactonization to give the tricyclic carboxylic acid 58 (94). This compound has four [C(15), C(16), C(17), and C(18)] of the five contiguous stereocenters of the reserpine E-ring in place. Acid 58 was converted to diazoketone 59 which underwent Wolff rearrangement followed by tryptamine trapping to afford amide 60. Bischler-Napieralski cyclization of this substance afforded the tetracyclic... 

An interesting D-ring closure was used by Pakrashi and his coworkers to synthesize normalindine (466) and norisomalindine (467) (Scheme 3.81) (130). Imine 462, prepared by condensation of tryptamine and 3-acetylpyridine, was reduced and the formed amine was acetylated to afford amide 463. Bischler-Napieralski cyclization of 463 provided tetracyclic iminium bis-perchlorate salt 464 which when treated with triethylamine and pivaloyl chloride underwent a second cyclization to yield the pentacyclic enamine 465. Reduction of the olefinic group in 465 afforded the desired azayohimbines, 466 and 467. 

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