“…Other syntheses of 2 including cycloaddition steps, e.g., are too long and low in yield. − To avoid these disadvantages, a new access to indolo[2,3- a ]pyrrolo[3,4- c ]carbazoles is elaborated. An adequate precursor should be a bis-indolo-γ-butyrolactam 8e (Scheme ).…”
Indolo[2,3-a]pyrrolo[3,4-c]carbazoles were isolated from nature, e.g., from low plants, especially fungi, as structurally rare natural substances. Responsible for naming and also the most important representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its aglycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrrolidin-2-ones, a group of compounds with many interesting biological properties are related to staurosporinone. The most important property is the inhibition of protein kinase C (PKC), so that this antiproliferative agent can interfere with the cell cycle. The synthetic strategy, developed by us, allows the synthesis of pyrrolidin-2-ones by an intermolecular Michael addition, starting from nitroethene derivatives and substituted acetate Michael donors. With this method also enantioselective syntheses can be carried out using chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the lactam partial structure, which is essential for the biological activity, is obtained. Besides indole substituents, which were used for the synthesis of staurosporinone, substituted indole-, phenyl-, and pyridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably high diastereoselectivity and enantioselectivity ((S)-pyrrolidine) could be detected. Just like the total synthesis of staurosporinone within three steps, the easiest and shortest approach reported up to now, with good to moderate yields, this sequence allows highly diastereoselective syntheses, which open the easy access to a new family of compounds.
“…Other syntheses of 2 including cycloaddition steps, e.g., are too long and low in yield. − To avoid these disadvantages, a new access to indolo[2,3- a ]pyrrolo[3,4- c ]carbazoles is elaborated. An adequate precursor should be a bis-indolo-γ-butyrolactam 8e (Scheme ).…”
Indolo[2,3-a]pyrrolo[3,4-c]carbazoles were isolated from nature, e.g., from low plants, especially fungi, as structurally rare natural substances. Responsible for naming and also the most important representative of this type is staurosporine (1), isolated from Streptomyces staurosporeus, and its aglycon (2), also known as staurosporinone or K-252c. 3,4-Disubstituted pyrrolidin-2-ones, a group of compounds with many interesting biological properties are related to staurosporinone. The most important property is the inhibition of protein kinase C (PKC), so that this antiproliferative agent can interfere with the cell cycle. The synthetic strategy, developed by us, allows the synthesis of pyrrolidin-2-ones by an intermolecular Michael addition, starting from nitroethene derivatives and substituted acetate Michael donors. With this method also enantioselective syntheses can be carried out using chiral auxiliaries. After reduction of the nitro group and subsequent lactamization, the lactam partial structure, which is essential for the biological activity, is obtained. Besides indole substituents, which were used for the synthesis of staurosporinone, substituted indole-, phenyl-, and pyridyl- as well as enantiomerically pure (S)-proline derivatives were used. Here, considerably high diastereoselectivity and enantioselectivity ((S)-pyrrolidine) could be detected. Just like the total synthesis of staurosporinone within three steps, the easiest and shortest approach reported up to now, with good to moderate yields, this sequence allows highly diastereoselective syntheses, which open the easy access to a new family of compounds.
“…Elaboration of 16 to the corresponding indolocarbazole finds close precedent in the literature,2a thus establishing a viable synthetic route to proximally substituted indolopyrrolocarbazoles (Scheme ). 5 Strategy for the Regiocontrolled Synthesis of Indolopyrrolocarbazoles Functionalized at the Nitrogen Proximal to the Carbonyl…”
[reaction: see text] Monosubstituted isomerically pure indolopyrrolocarbazole precursors have been prepared via palladium-catalyzed asymmetric allylic alkylation methodology, employing both achiral cyclopentenyl electrophiles and chiral glycal derivatives. Chemoselective allylation of (bis)indole lactam pro-aglycon 3 allows access to N-distally substituted indolopyrrolocarbazole derivatives; glyoxamide precursor 14 provides entry into N-proximally substituted derivatives.
“…The rst protecting group free synthesis of the aglycone 10, was completed by Moody and co-workers in 1990 (Scheme 5). 38,39 The approach centred on intramolecular Diels-Alder decarboxylation sequence from pyranone 42, prepared in 6 steps from the commercially available enal 18. 40,41 Allylic amine fragment 39 was prepared by Luche reduction of 18, then coupling of the resulting cinnamyl alcohol with phthalimide under Mitsonobu conditions and hydrazinolysis.…”
Section: The Indolocarbazole Alkaloids and Their Discoverymentioning
Syntheses of indolo[2,3-a]pyrrolo[3,4-c]carbazole natural products are discussed, including staurosporine aglycone, arcyriaflavins, and glycosylated derivatives including staurosporine, rebeccamycin and K252A.
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