The bromoquinone annulation reaction: a formal total synthesis of EO9

Abstract

The following report describes a one-pot regiospecific annulation reaction in the production of a highly advanced EO9 precursor. This intermediate is modified in what constitutes the shortest total synthesis of the EO9 antitumor drug.

Synthesis of Indolequinones from Bromoquinones and Enamines Mediated by Cu(OAc)2·H2O

“…The inferior reactivity of 2-bromo-5-methoxybenzoquinone, compared with the 6-methoxy isomer, is noteworthy but is consistent with the results reported by Murphy and co-workers and with the proposed mechanism which begins with 1,4-addition of the enamine through carbon to the 3-position of the bromoquinone and reoxidation (Scheme ). Premature termination of the reaction afforded the intermediate uncyclized enaminoquinone 21 , observed in all reactions as a red component which eventually converted to the product under the reaction conditions.…”

“…In their approach to the synthesis of mitosenes related to MMC, Luly and Rapoport reported the reaction of 2,3-dibromo-1,4-benzoquinones with enamine derivatives to give the indolequinone core structure . Subsequently, in their synthesis of EO9 and related mitosenes, Murphy et al reported a synthesis of indolequinone esters by oxidative annulation of monobromoquinones with enamines, using catalytic amounts of copper(II) bromide and utilizing air as the terminal oxidant. , Although this appears to be an attractive route, the procedure proved extremely sensitive to structural changes in the substrates and generally gave unsatisfactory yields in our hands. Therefore, we initiated a series of optimization experiments using the reaction of 2-bromo-6-methoxy-1,4-benzoquinone 4 and methyl N -methylamino-crotonate 5 (to give the indolequinone 6 ) under a range of conditions employing copper(II) salts (Table ).…”

Recent Advances in the Synthesis of Indoles with Partially Hydrogenated Benzene Ring (Tetrahydroindoles)

“…The reaction can be carried out on a multi-gram scale, providing access to biologically interesting structures. The lower reactivity of 2-bromo-5-methoxybenzoquinone compared to 6-methoxy isomer 213a deserves attention, but it is consistent with the results obtained by Murphy et al ., 111 and with the proposed mechanism that begins with 1,4-addition of enamine via carbon to the position of 3 bromoquinone and reoxidation (Scheme 65 ). Premature cessation of the reaction gives an intermediate uncyclized enaminoquinone 216 , which eventually develops into a product 215a under reaction conditions.…”