Synthesis of N-Protected Staurosporinones

Abstract

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.

Synthesis of Functionalized Heterocycles via Oxidative Carbonylation

“…In 2007, they applied this methodology to the synthesis of N-protected staurosporinones [101]. In 2011, Rovis and co-workers developed a rhodium(III)-catalyzed oxidative carbonylation of benzamides to form phthalimides with Ag 2 CO 3 as the oxidant (Scheme 34a).…”

Oxidative Carbonylation as a Powerful Tool for the Direct Synthesis of Carbonylated Heterocycles

“…Dialkylamines 71 (Scheme 46), with suitably placed phenyl groups on their alkyl chains, were converted into benzolactams 72 when allowed to react with CO (1 atm) in the presence of Pd(OAc) 2 /Cu(OAc) 2 as the catalytic system and O 2 as the oxidant. [58] Scheme 48. [58] More recently, conditions for the conversion of β-arylalkylamines 74 (Scheme 48) into the corresponding benzolactams 75 at room temperature have been developed, [59] and N-unsubstituted benzolactams 77 (Scheme 49) have also been obtained from β-arylalkylamines 76 with use of Pd(OAc) 2 as catalyst and benzoquinone as oxidant.…”

“…[36o] This reaction has recently been applied to the synthesis of the natural product staurosporinone (73, Scheme 47). [58] More recently, conditions for the conversion of β-arylalkylamines 74 (Scheme 48) into the corresponding benzolactams 75 at room temperature have been developed, [59] and N-unsubstituted benzolactams 77 (Scheme 49) have also been obtained from β-arylalkylamines 76 with use of Pd(OAc) 2 as catalyst and benzoquinone as oxidant. [60] Scheme 46.…”

Natural product leads for drug discovery: Isolation, synthesis and biological evaluation of 6-cyano-5-methoxyindolo[2,3-a]carbazole based ligands as antibacterial agents

“…The free indole nitrogen as well as the phenolic hydroxyl group of intermediates 6b and 6c were methylated to give the corresponding compounds 7a and 7b . Compound 7b was subsequently treated with AlCl 3 in anisole at 110 °C to remove the N -benzyl group to form 8 in quantitative yield 15. The nitrile group at the 6-position of the indolo[2,3- a ]carbazole 1b was readily hydrolyzed in the presence of hydrogen peroxide to give the new carboxamide 9 .…”