Tjipanazoles

The tjipanazoles (18, 19a-d, 20a-b) a group of A-glycosides of indolo-[2,3-a]carbazole, have been isolated from the moderately antifungal extract of the blue-green alga Tolypothrix tjipanasensis. These alkaloids do not exhibit antitumor or protein kinase C (PKC) inhibitory activity, which is in contrast with the... 

In synthesis of the alkaloid tjipanazole E (19b), the required symmetric dichloro-indolo[2,3-fl]carbazole 20a was obtained in a two-step procedure starting fi-om 4-chlorophenylhydrazine hydrochloride and 1,2-cyclohexanedione employing a Fischer indolization. Subsequent attachment of an acetyl-protected glucopyranosyl moiety to one of the nitrogens, followed by cleavage of the protective groups with ammonia in methanol, produced the desired natural product (91X7739). 

Comparison of the H-NMR spectrum of tjipanazole G1 (363) with that of tjipanazole Cl (362) indicated the absence of a chlorine atom at C-3 of the aglycon. This was also clear from the H-NMR spectrum by the presence of an additional, mutually ortho-coupled (/=8.4Hz), triplet proton signal at S 7.22, assignable to the C-3 proton. Based on these spectral data and the close structural similarity to tjipanazole Cl (362), the structure 363 was assigned to tjipanazole G1 (329) (Scheme 2.94). 

Comparison of the H-NMR spectrum of tjipanazole G2 (366) with that of tjipanazole G1 (363) showed the presence of a similar structure, except for the difference in the configuration of the 2 -methyl group of the sugar moiety, showing... 

The H-NMR spectrum of tjipanazole FI (371) was very similar to that of tjipanazole Cl (362) (see Scheme 2.94), except for the nature of the sugar unit... 

Bonjouklian and Moore et al. reported the total synthesis of the tjipanazoles D (359) and E (370) to support the assigned structures for these natural products. Condensation of 2 equivalents of 4-chlorophenylhydrazine hydrochloride (1327) with 1,2-cyclohexanedione (1328) in the presence of air and step-wise Fischer indolization provided tjipanazole D (359) in 54% yield. Coupling of 359 with... 

Gilbert and Van Vranken described the synthesis of tjipanazole F2 (372) by introduction of the halide and the glycosidic substituent at the heterocyclic skeleton without the use of protecting groups and with complete control of regioselectivity... 

In the following year, this method was also applied to the total synthesis of tjipanazole FI (371) (784). For this synthesis, the required bisindole 1444 was obtained starting from 5-chloroindole (1440) in three steps and 47% overall yield. Acylation of 1440 with oxalyl chloride led to the glyoxylic acid chloride 1441. Transmetalation of indolylmagnesium bromide with zinc chloride, followed by addition of the acid chloride, provided the ot-diketone 1443. Exhaustive reduction of 1443 with lithium aluminum hydride (LiAlFl4) afforded the corresponding bisindolylethane 1444. Executing a similar reaction sequence as shown for the synthesis of tjipanazole F2 (372) (see Scheme 5.243), the chloroindoline (+ )-1445 was transformed to tjipanazole FI (371) in two steps and 50% overall yield (784) (Scheme 5.244). 

Kuethe et al. reported the synthesis of the tjipanazoles D (359), I (360), B (369), and E (370) starting from the nitro derivative 1496 (796). This route involves the synthesis of 2,2 -bisindoles, followed by a two-carbon insertion through condensation with (dimethylamino)acetaldehyde diethyl acetal to afford the indolocarbazole ring. 

Reaction of the TMS-nitro compound 1496 and the indole carboxaldehyde 1497 with a catalytic amount of TBAF led to the desired alcohol 1498, which, on further treatment with TFAA, followed by elimination of the corresponding trifluoroacetate with DBU, afforded the frans-stilbene 1499. Reductive cyclization of 1499 under Cadogan-Sundberg conditions afforded the bisindole 1500. Finally, condensation of 1500 with (dimethylamino)acetaldehyde diethyl acetal led to tjipanazole D (359) in 71% yield (796) (Scheme 5.255). 

Analogous to the aforementioned method, starting from the same nitro derivative 1496 and the indole carboxaldehyde 1501, tjipanazole I (360) was obtained in five steps and 28% overall yield (796) (Scheme 5.256). 

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