Tjipanazole synthesis

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). 

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. 

The same authors also reported the total synthesis of tjipanazole B (369) in 66% overall yield, in two steps, by reacting tjipanazole D (359) with a-D-xylopyranosyl chloride (1503) in a biphasic mixture of MTBE and 45% aqueous KOH and Aliquat 336, followed by hydrogenation with Pd(OH)2 (796). Similarly, reaction of tjipanazole D (359) with a-D-glycopyranosyl chloride (1504) led to tjipanazole E (370) in two steps and 77% overall yield (796) (Scheme 5.257). 

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