Aglycone-indolocarbazole

In a related study, the precursor 41 could be amiulated either by irradiation or by treatment with palladium acetate in acetic acid to provide indolocarbazoles 42 and 43 in yields of 37% and 55%, respectively (Scheme 8). Both products were eventually deprotected efficiently to give 44 and transformed further under reductive conditions to staurosporinone 45, the aglycone of 8, Alternatively, a shorter route encompassing deprotection of 41, followed by cychzation by irradiation in the presence of iodine and subsequent reduction, gave 45 in an even better overall yield (98T6909). 

The required furanosylated indolocarbazole 1380 should be readily available by reduction of 1379, a precursor of (+)-K-252a (330). For the synthesis of (+)-K-252a (330) a single-step cycloglycosidation of the selectively protected aglycon 1381 with an appropriate furanose was planned. The protected aglycon 1381 should be readily available by a rhodium-catalyzed coupling of 2,2 -bisindole 1384 with the a-diazo-p-keto-y-lactam 1382 (Scheme 5.232). 

Scheme 20.1 Clycosylation of indolocarbazoles by feeding appropriate aglycones to the fermentation broth of ngt-expressing streptomycetes.

The synthetic strategy employs novel rhodium carbenoid chemistry in the construction of both the indolocarbazole aglycone 2 and the carbohydrate moiety 3 <97JA9641>. For the total synthesis of pyranosylated indolocarbazoles ((+)-RK286c, (+)-MLR-52, (+)-stauroporine, (-)-TAN-10309) see <97JA9652>. The total synthesis of 4, an enantiomer of the marine furanocembrane rubifolide, starting with an allene was described <97JOC4313>. 

Recently still another class of compounds of fused carbazole alkaloids has been recognized. Two particulary interesting members of this class are staurosporine (8a) and its aglycon (8b), both potent inhibitors of protein kinase C. The chemistry of the indolocarbazole alkaloids ha recently been thouroughly reviewed " and will therefore not be discussed in this treatise. 

The indolocarbazole acceptor is generally a weaker nucleophile than the bis(indolyl)-malei-mide or indole acceptor, which limits application of established glycosylation methodologies to the indolocarbazole aglycones. 

Staurosporine can be divided into two distinct parts the "northern" indolocarbazole aglycon and the "southern" carbohydrate portion of the molecule, as shown in Figure 6. One can envision that by so dissecting the molecule, a convergent S3/nthetic approach would be possible in which a lactam-protected derivative of aglycon could be coupled with a bis-gjycal derivative (no commitment is made as to the functional nature of Rj or R2). 

From Figure 7 one may infer that aglycon 2 is itself a natural product, commonly referred to as staurosporinone or K-252c. Because it constitutes a major unit of many indolocarbazole natural products, several approaches to its S3mthesis have been developed [31-32]. Classified by the last covalent bond(s) formed, these approaches include cycloaromatization (A), double nitrene C-H insertion (B, B ), nitrene C-H insertion (B ), maleimide reduction (C), and diazolactam initiated cycloaromatization (D). 

Synthetic studies on indolocarbazoles Total synthesis cf staurosporine aglycon... 

Mohankrishnan et al s)mthesized staurosporine aglycon and its analogues with 28-36% overall yield, using 2-methylindole (110) as synthetic precursor [50]. The key steps for the s)mthesis of indolocarbazole alkaloids involved electrocychzation and nitrene insertion reactions as depicted in Schemes 16 and 17. 

Rajeshwaran GG, Mohanakrishnan AK. S3mthetic studies on indolocarbazoles Total synthesis of staurosporine aglycon. Qrg. Lett. 2011 13 (6) 1418-1421. 

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