Dihydroxylation Studies of Isoquinolinones: Synthesis of the EF-Ring of Lysolipin I

Abstract

Inspired by the potent polycyclic xanthone antibiotic Lysolipin I, a general study on asymmetric dihydroxylation reactions of variously substituted isoquinolinones was performed. Different isoquinolinones were efficiently prepared, either by a Pomeranz-Fritsch type condensation or a Curtius rearrangement. Under a broad variety of conventional oxygenation procedures they proved very unreactive. However, either by suitable substitution of the appending aromatic ring or more forcing conditions a dihydroxylation could finally be performed, which allowed for synthesis of the EF-ring of Lysolipin I.

Modular Synthesis of Halogenated Xanthones by a Divergent Coupling Strategy

“…Both substrates may be alkynylated by a two-step procedure involving initial coupling with TMS-protected alkyne 34 in the presence of catalytic amounts of Pd­(PPh 3 ) 4 , followed by KF-mediated removal of the silyl group. − The resulting homologated xanthones 35 and 36 may then be coupled with various aryl substrates, such as 37 and 38 , giving biaryl derivatives 39 – 42 , likewise in useful to excellent yield (47–96% over 3 steps) . Notably, also a lysolipin-type isoquinoline moiety 43 may be attached toward 44 with excellent conversion (91% over three steps from 33 , Scheme , bottom part), further demonstrating the applicability of these substrates, also for complex target synthesis.…”

“…6−8 In detail, elaborate xanthones bearing a bromide in either the 6-or the 7-position were required, to allow for a flexible coupling strategy to access the central phenanthrene core. Herein, we report the design, development, and application of a divergent coupling strategy to access different 6-bromo of the 7-bromoxanthones (3)(4)(5)(6) starting from the same o-vanillin derivatives (7,8) and dibromoquinone 9 and the further elaboration of these xanthones by sequential Sonogashira couplings.…”

“…As exemplified by lysolipin I ( 1 , Figure ), elaborate xanthones present key structural features in a wide variety of complex natural products as well as a high number of bioactive agents. − Consequently, the development of efficient synthetic strategies toward these biologically important heterocycles presents an important research objective from the perspective of medicinal and synthetic chemistry. While a wide variety of different strategies to specific xanthones have been developed, these procedures still leave room for further improvement, in particular with respect to modularity and divergence. − As part of our studies to realize a first total synthesis of lysolipin I ( 1 ), a highly potent polycyclic antibiotic of bacterial origin, we became interested in the design of a flexible route to differently substituted halogenated xanthones. − In detail, elaborate xanthones bearing a bromide in either the 6- or the 7-position were required, to allow for a flexible coupling strategy to access the central phenanthrene core. Herein, we report the design, development, and application of a divergent coupling strategy to access different 6-bromo of the 7-bromoxanthones ( 3-6 ) starting from the same o -vanillin derivatives ( 7 , 8 ) and dibromoquinone 9 and the further elaboration of these xanthones by sequential Sonogashira couplings.…”