Pyrrolo carbazoles

The interest in indolocarbazoles began in the early 1950s with the first rational synthetic approaches. Since then, this interest has escalated dramatically as numerous derivatives of indolo[2,3-a]carbazole (1) have been isolated from various natural sources. These derivatives were demonstrated to possess highly potent and diverse biological effects, prompting novel efforts in the area. In particular, derivatives of indolo[2,3-n]pyrrolo[3,4-c]carbazole, such as the alkaloid staurosporine (8), have attracted much attention. 

Indolocarbazole glycosides have attracted considerable interest over the years, as most indolo[2,3-fl]pyrrolo[3,4-c]carbazole alkaloids possess this structural feature. These systems are beyond the scope of this review however, there are several studies where glycosides of the parent system 1 have been investigated, in some... 

Indolo[3,2-fl]pyrrolo[3,4-c]carbazoles 120 have been obtained in one step from indole and the corresponding maleimides in acetic acid, with coformation of the Michael adducts 121 (Scheme 15). This reactitai required careful temperature control in order to obtain the desired product ratios. An alternative independent synthesis of compounds 120 could also be accompKshed from 2,3 -biindolyl (115) andsuitable maleimides in hot acetic acid (99T2363). The system 120 where R = H has also been reported as a minor product during studies toward a synthesis of the alkaloid arcyriaflavin A (95TL2689). 

Hill described the Pd(OAc)2-oxidative cyclization of bisindolylmaleimides (e.g., 49) to indolo[2,3-a]pyrrolo[3,4-c]carbazoles (e.g., 50) [69], which is the core ring system in numerous natural products, many of which have potent protein kinase activity [70]. Other workers employed this Pd-induced reaction to prepare additional examples of this ring system [71, 72]. Ohkubo found that PdClj/DMF was necessary to prevent acid-induced decomposition of benzene-ring substituted benzyloxy analogues of 49, and the yields of cyclized products under these conditions are 85-100% [71]. 

The rearrangement of hexahydroazocino [4,3-1 ] indole 101 into pyrrolo[3,2-flj-carbazole 102 under Wolff-Kishner reaction conditions is also described in the publication (Scheme 28 84H(22)561). The reaction is a special case of cleavage of compounds related to gramine. 

The UV spectrum (/Imax 229, 288, 324, 391, and 475 nm) of the pyrrolo[2,3-c]carbazole alkaloid 290 showed the presence of a pyrrolo[2,3-c]carbazole framework with a spirolactone structure. The H-NMR spectrum indicated the presence of two... 

The UV spectrum (/Imax 229, 289, 324, 391, and 475 nm) of the pyrrolo[2,3-c]carbazole alkaloid 291 was identical to that of 290, indicating the presence of a similar pyrrolo[2,3-c]carbazole spirolactone framework. Comparison of the spectral data of this isolate with those of the pyrrolo[2,3-c]carbazole alkaloid 290 indicated it to be an acid form of 290. This was further established by the chemical conversion of 291 to the corresponding 7-hydroxy derivative. Based on these spectral data, and the close structural similarity to 290, the structure 291 was assigned to this compound (250) (Scheme 2.72). 

Previously in the literature, for simplicity, under indolo[2,3-fl]carbazole natural products, only the indolo[2,3-fl]carbazoles with and without the pyrrolo[3,4-c]ring were considered. The recent past has witnessed an explosive growth of these natural products. Due to this, and the difference in the aglycon framework, in this article we have classified the indolo[2,3-fl]carbazoles with a pyrrolo[3,4-c]ring as indolo[2,3-fl]pyrrolo[3,4-c]carbazole alkaloids, and the indolo[2,3-fl]carbazoles without a pyrrolo[3,4-c]ring as simple indolo[2,3-fl]carbazole alkaloids. 

The majority of indolocarbazole alkaloids, isolated so far from nature, are derivatives of the indolo[2,3-fl]pyrrolo[3,4-c]carbazole ring system 292. They have been isolated from soil organisms, slime molds, and marine sources (3,7,8,252-255), and have shown a broad range of potent biological activities, such as antifungal, antimicrobial, antitumor, and antihypertensive activity (3,7,256-260,267-270). Their activity as potent inhibitors of protein kinase C (PKC) has received special attention, and was the focus of several investigations (8,257,258,271-280). The history of these natural products dates back about 30 years (Scheme 2.73). 

The UV spectrum [Amax 243, 267 (sh), 292, 322 (sh), 335, 356, and 372 nm] of (+)-staurosporine (AM-2282) (295) was very similar to that of staurosporinone (293), indicating the presence of a similar indolo[2,3-fl]pyrrolo[3,4-c]carbazole framework. The IR spectrum indicated the presence of an NH band at v ax 3500 cm and an amide band at 1675 cm . The structure and relative stereochemistry of this isolate were established by X-ray crystallographic analysis of the methanol solvate (282,283). The structure 295, indicating the presence of an indolocarbazole subunit, wherein two... 

The UV spectrum [7max 238, 256 (sh), 293 (sh), 314, 362 (sh), and 390 (sh) nm] of rebeccamycin (337) indicated the presence of an indolo[2,3-fl]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. This was also discernible from its IR spectrum. The H-NMR spectrum indicated the presence of an amide NH at 8 11.37 and an indole NH at 6 10.30, in addition to signals for aromatic protons and a sugar moiety. Unlike (+)-staurosporine (295) (see Scheme 2.74), where the lactam function deshielded only the ortho C-4 proton, the C-4 and C-8 aromatic protons in rebeccamycin are both deshielded due to the anisotropic deshielding effect of the phthalimide function. 

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