Synthesis of heterocyclic natural products: Model studies towards diazonamide A

Model studies towards the total synthesis of the cytotoxic marine natural product diazonamide A are described. The approach uses rhodium(I1) catalysed reactions of diazocarbonyl compounds in 4 key steps; the construction of the oxazole rings by the rhodium(I1) catalysed addition of diazocarbonyl compounds to nitriles, and of the indole and benzofuran tinits by rhodium(l1) mediated intramolecular aromatic C-H insertion reaction\. Recently the isolation of a number of oxazole containing natural products, particularly from marine sources, has caused a renewed interest in the chemistry of oxazoles. Naturally occurring oxazoles range in structure from relatively simple 2,s-substituted derivatives such as pimprinine (4.v.) to more complex bis-oxazoles such as the diazonamides. The diazonamides, exemplified by diazonamide A, isolated from the ascidan Diazona chinensis,( 1) show potent anticancer activity, and their unique his-oxazolylindole structure coupled to a dihydrobenzofuran makes them attractive targets for synthesis. We now report the results of model studies towards diazonamide A, using rhodium(1l) catnlysed reactions of diazocarbonyl conipounds in 4 key steps, viz. the construction of the oxazole rings by the rhodiuni(l1) catalysed addition of diazocarbonyl compounds to nitriles, arid of the indole and benzofuran units by rhodium(1l) mediated intramolecular aromatic C-H insertion reactions. 4 steps involve diazocarbonyl chemistry 2 oxa~o lcs by addi~iori to nitrilcs C-10 C-I2 by inlramolccular carbcnoid C-H insertion C-23 C-24 by ~~ivarnoIccuIar carbcnoid C-H insertion Diazonamide A (R = COCH(NH2)CHMe? Synthesis of 3-(Oxazol-5-yl)indoles The formation of oxazoles by reaction of diazocarbonyl compounds with nitriles can be effected under thermal, photochemical, Lewis acid or transition-metal catalysis, although the latter conditions are often the 2107 2108 C. J. MOODY eta/. higher yielding and most synthetically useful.(2) I n previous studies we have shown that the rhodium(I1) catalysed addition of simple diazocarbonyl compounds to nitriles can be extended to include sulfonyl, phosphonyl and nitrile containing diazo compounds, and i n the last case, the resulting 4-cyanooxazole can be elaborated into a bis-oxazole in 2 further steps (Scheme 1).(3) Scheme 1 In order to apply this methodology to the oxazolylindole fragments of diazonamide A, we required a route to diazoacetyl indoles. The N-protected diazoacetylindole 1 was readily prepared from 3-acetylindole using the modified diazo transfer procedure developed by Danheiser.(4) Rhodium(I1) acetate catalysed decomposition of 1 in boiling acetonitrile gave the desired 3-(oxazol-S-yl)indole 2 (R = Me) in 40% yield, deprotection of which with sodium methoxide in methanolRHF gave the oxazolylindole 3 (R = Me) (74%). Interestingly, the oxazolylindole 3 (R = Me) is a natural product, pimprinine.(5) The closely related oxazolylindole alkaloid piniprinethine 3 (R = Et) was also prepared from 1 by a similar route, although in this case the use of rhodiuni(11) trifluoroacetamide, a more active catalyst for certain carbenoid transformations,(6) was necessary. Thus reaction of 1 with propionitrile at room temperature in the presence of rhodium(I1) trifluoroacetdmide gave the oxazolylindole 2 (R = Et) in 90% yield, deprotection of which as above gave piniprinethine (78%) (Scheme 2 ) . LiHMDS, THF, -78°C CF~CO~CHZCFR, M s N ~ , Et3N u Boc N I 3 Boc 1