The Stille coupling reaction of stannylindole 12 with 4-iodoimidazole 13 (or 24) in the presence of PdCl 2 (PPh 3 ) 2 gave the corresponding indole-imidazole coupling product 14 (or 25), thereby affording a new synthetic approach to the alkaloid granulatimide (7), isolated from the Brazilian ascidian Didemnum granulatum, as well as its structural analogues, 10-methylgranulatimide (23), 17-methylgranulatimide (30), 10,17-dimethylgranulatimide (31).
Granulatimide (1) and isogranulatimide (2), isolated from the Brazilian ascidian Didemnum granulatum, [1][2][3] are without precedent among natural alkaloids having indole/ maleimide/imidazole-containing aromatic heterocyclic skeletons, and they show strong activity as G2 checkpoint inhibitors.4) Total syntheses of 1, 2, and their structural analogues, isogranulatimide A (3), isogranulatimide B (4), and isogranulatimide C (6) have already been reported by Piers and colleagues. 1,5) In a previous paper, we presented a new synthetic route to granulatimide (1), 10-methylgranulatimide (7), 17-methylgranulatimide (8) and 10,17-dimethylgranulatimide (9).6) The latter analogues are congeners of the structural isomers 10, 11 and 12 in the imidazole moiety (Fig. 1).Previous syntheses of granulatimide and its analogues employed the Stille coupling reaction of stannylindole with 4-iodoimidazole in the presence of PdCl 2 (PPh 3 ) 2 , affording the 2,4Ј-indole-imidazole coupling product as a key intermediate. Subsequent reaction of indolyl Grignard reagents with 3,4-dibromomaleimide gave the condensation product, which was converted to granulatimide analogues by photocyclization (route A). Here we wish to report the preparation of new analogues of 1, 10-methylgranulatimide (10), 15-methylgranulatimide (11), and 10,15-dimethylgranulatimide (12), as well as 10-methylisogranulatimide B (5), by the use of 5-iodoimidazole instead of 4-iodoimidazole in the same synthetic strategy (route B) (Chart 1). Results and DiscussionTo obtain the new granulatimide analogues 10, 11, 12 and the 2,5Ј-indole-imidazole coupling product for further structural manipulation, we needed to replace the 4-iodoimidazole moiety with a 5-iodoimidazole derivative. Thus, introduction of imidazole into compound 14 (or 27) was carried out using 1-methoxy-2-tributylstannylindole (13) (Chart 2).The 5-iodo-1-methyl-2-phenylthioimidazole (14) and 5-iodo-1-methoxymethyl-2-phenylthioimidazole (27) were synthesized from 1-methylimidazole (or imidazole) according to reported methods.7) The stannyl derivative 13 was itself prepared from 1-methoxyindole 8,9) by regioselective lithiation with n-BuLi 10-12) and subsequent reaction with chlorotributylstannane.13) The Stille coupling reaction 14,15) of 13 with the imidazole 14 in the presence of PdCl 2 (PPh 3 ) 2 in toluene afforded the 2,5Ј-indole-imidazole coupling product 15 in 65% yield.On the other hand, the reaction of 13 with the imidazole 27 under similar reaction conditions, but in benzene instead of toluene, afforded 28 in 64% yield. Subsequent deprotection of the 1-methoxy group in 15 and 28 was readily achieved with Mg-MeOH to give, in 92 and 76% yields, 5-(1H-indol-2-yl)-1-methyl-2-phenylthio-1H-imidazole (16) and 5-(1H-indol-2-yl)-1-methoxymethyl-2-phenylthio-1H-imidazole (29), key intermediates for synthesizing new analogues. To confirm the coupling reaction, compounds 15 and 29 were subjected to a heteronuclear multiple bond connectivity The Stille coupling reaction of the stannylindole 13 with the 5-iodoimi...
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Alkaloids Alkaloids U 0600Synthesis of Granulatimide Positional Analogues. -The Stille coupling of an in situ prepared stannylindole with the 5-iodoimidazole (II) yields the corresponding coupling product (III) thereby affording a synthetic approach to granulatimides (VIII), (XI) and (XIII). -(YOSHIDA, T.; NISHIYACHI, M.; NAKASHIMA, N.; MURASE*, M.; KOTANI, E.; Chem. Pharm. Bull. 51 (2003) 2, 209-214; Showa Pharm. Univ., Machida, Tokyo 194, Japan; Eng.) -M. Paetzel 30-224 2003 Alkaloids
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