Synthesis of isoindolobenzazepine alkaloids based on radical reactions or Pd(0)-catalyzed reactions.

Methods for synthesis of a ring system characteristic of isoindolobenzazepine alkaloids were studied. Synthesis of lennoxamine and a formal synthesis of chelenine were accomplished in a short route via radical or Pd(0)-catalyzed cyclization as the key step. An altenative approach based on a radical migration of a cyano group or Pd(0)-catalyzed carbonylation was also developed for both alkaloids.

On the synthesis of protopine alkaloids.

For the synthesis of protopine alkaloids, we studied a reaction sequence based on a ring enlargement of indeno[2,1-a][3]benzazepines by a singlet oxygen oxygenation, followed by conversion of an amide carbonyl group of the resultant 10-membered keto-lactam to a methylene group, which is the last step for completion of the synthesis. The key substances, indeno[2,1-a][3]benzazepines, were prepared by Bischler-Napieralski cyclization of alkoxy-substituted 1-(2-bromobenzyl)-3-benzazepin-2-ones. Steric effects of the substituents in this synthesis were examined.

Synthesis of N-protected staurosporinones.

We report a method for the synthesis of N-protected staurosporinones, which are useful for the synthesis of indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids and related compounds. An interaction of gramine methiodide (2) with 3-(N-benzyl)indolylacetonitrile (3) in the presence of t-BuLi, followed by a CF3COOH-catalyzed intramolecular indole-indole coupling and dehydrogenation with DDQ, produced 5-cyanoindolo[2,3-a]carbazole 6 almost quantitatively. Reduction of its cyano group followed by N-benzylation produced N-benzylaminomethylindolo[2,3-a]carbazole 8b, which was subjected to Pd(OAc)2-catalyzed direct aromatic carbonylation to give N-protected staurosporinone 9b. Treatment with AlCl3 in anisole removed N-benzyl groups to afford staurosporinone quantitatively.

Pd(OAc)2-catalyzed carbonylation of amines.

A phosphine-free catalytic system [Pd(OAc)2-Cu(OAc)2-air] induced a substrate-specific carbonylation of amines in boiling toluene under CO gas (1 atm). Symmetrical N,N'-dialkylureas were obtained by the carbonylation of primary amines. N,N,N'-Trialkylureas were selectively formed by addition of a secondary amine to the above reaction vessel. Secondary amines did not give tetraalkylureas. However, dialkylamines with a phenyl group on their alkyl chains, such as N-monoalkylated benzylic amine or phenethylamine derivatives, underwent a direct aromatic carbonylation to afford five- or six-membered benzolactams. In the carbonylation, the chelation effect or steric repulsion between Pd(II) and the meta-substituent in the ortho-palladation and the ring sizes of cyclopalladation products that were formed prior to carbonylation were found to generate good site selectivity and increase the reaction rate. In contrast, carbonylation of omega-arylalkylamines with a hydroxyl group gave neither ureas nor benzolactams but instead produced 1,3-oxazolidinones smoothly. Hydrochlorides of amines also underwent carbonylation to afford the corresponding amides under the conditions used. This procedure made it possible to prepare ureas of amino acid esters and N-alkylcarbamates in practical yields.

Preparation of benzolactams by Pd(OAc)2-catalyzed direct aromatic carbonylation.

We developed a new method for Pd(II)-catalyzed direct aromatic carbonylation in a phosphine-free catalytic system using Pd(OAc)2 and Cu(OAc)2 in an atmosphere of CO gas containing air. The carbonylation proceeded with ortho-palladation, inducing a remarkable site selectivity to afford a variety of five- or six-membered benzolactams from secondary omega-arylalkylamines, such as N-alkylbenzylamines or N-alkylphenethylamines.

Pd(0)-catalyzed conjugate addition of benzylzinc chlorides to alpha,beta-enones in an atmosphere of carbon monoxide: preparation of 1,4-diketones.

Pd(0)-catalyzed conjugate addition of benzylzinc chloride to methyl vinyl ketone in the presence of chlorotrimethylsilane and lithium chloride in an atmosphere of carbon monoxide at room temperature afforded 1-phenyl-2,5-hexanedione monosilyl enol ether. In this catalytic carbonylation, four components are connected in one reaction. Successive acidic workup generated a variety of 1,4-diketones from substituted benzylzinc chlorides or related compounds and alpha,beta-enones. Some products were converted to cyclopentenones or five-membered heterocyclic compounds containing an N, O, or S atom.

Synthesis of Phthalideisoquinoline and Protoberberine Alkaloids and Indolo[2,1-a]isoquinolines in a Divergent Route Involving Palladium(0)-Catalyzed Carbonylation(1).

6,7,3',4'-Alkoxy-substituted 1-(2'-bromobenzoyl)-3,4-dihydroisoquinoline methiodides 17 were treated with sodium borohydride in methanol or acetic acid to give erythro-1-(2'-bromo-alpha-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolines 19. Treatment of 17 with lithium aluminum hydride in tetrahydrofuran gave the threo-isomer 20 in preference to the erythro 19. On the basis of studies on palladium(0)-catalyzed carbonylation of 2-bromo-3,4-dimethoxybenzyl alcohol to 6,7-dimethoxyphthalide, amino alcohol 19 or 20 was treated with a catalytic amount of palladium(II) acetate and triphenylphosphine in an atmosphere of carbon monoxide in the presence of chlorotrimethylsilane and potassium carbonate in boiling toluene to give the corresponding erythro- or threo-types of phthalideisoquinoline alkaloids 1 or 2, respectively. One-pot cyclization of the erythro-amino alcohols 19 was achieved by heating in N,N-dimethylformamide containing potassium carbonate to give 2,3,8,9- or 2,3,9,10-alkoxy-substituted 5,6-dihydroindolo[2,1-a]isoquinolines 3, which have a unique tetracyclic skeleton characteristic of dibenzopyrrocoline alkaloids. Similarly, palladium(0)-catalyzed carbonylation of 1-(2'-bromobenzyl)tetrahydroisoquinolines 21 in the presence of excess potassium carbonate was found to give 8-oxoberbines 22, which on reduction with lithium aluminum hydride can be converted to protoberberine alkaloids 4.