Directed ortho Metalation cross coupling, synthesis

V Snieckus, Combined Directed Ortho Metalation-Cross Coupling Strategies. Design for Natural Product Synthesis, PureAppl. Chem. 1994, 66, 2155-2158. 

Anctil, E. J. G., Snieckus, V. The directed ortho metalation-cross coupling symbiosis. Regioselective methodologies for biaryls and heterobiaryls. Deployment in aromatic and heteroaromatic natural product synthesis. J. Organomet. Chem. 2002, 653,150-160. 

Snieckus, V. Combined directed ortho metalation-cross coupling strategies. Design for natural product synthesis. PureAppl. Chem. 1994, 66,2155-2158. 

Kinsman AC, Snieckus V (1999) Directed ortho metalation-cross coupling route to indolo-4, 5-quinodimethanes. Synthesis of benz[e]indoles. Tetrahedron Lett 40 2453-2456... 

Snieckus and Fu reported a new general and regiospecific synthesis of 9-phenanthrols involving direct ortho-metalation, Suzuki cross-coupling, and an LDA-mediated directed remote metalation sequence (Eq. (11)) [27]. 

The disclosure of a one-pot directed ortho metalation-boronation and Suzuki-Miyaura cross-coupling of derivatized pyridines 44 to give substituted azabiaryls 45 provided an excellent protocol for the in situ utilization of pyridyl boronic acids whose isolation is known to be difficult <07JOC1588>. The disclosed method relies on the in situ compatibility of LDA and B(Oz-Pr)3 and proceeds in good to excellent yields for the multi-step process. The report details a comprehensive survey of pyridyl boronates and is expected to be of considerable value in the synthesis of bioactive molecules. 

The ready availability of ort/io-functionalized arylboronic acids by a direct ortho-metallation-boronation sequence (Scheme 2-45) provides a very useful synthetic link to the cross-coupling protocol. Snieckus has amply demonstrated that the sequence has considerable scope for the synthesis of unsymmetrical biaryls, heterobiaryls, and terphenyls [120]. 

V. Snieckus and co-workers developed a new carbamoyl Baker-Venkataraman rearrangement, which allowed a general synthesis of substituted 4-hydroxycoumarins in moderate to good overall yields. The intermediate arylketones were efficiently prepared from arylcarbamates via directed ortho metallation and Negishi cross coupling. The overall sequence provided a regiospecific anionic Friedel-Crafts complement for the construction of ortho-acyl phenols and coumarins. 

The synthesis of hippadine (44) and ungeremine (48) was performed by a combination of the directed ortho metallation and the modified Suzuki cross coupling reactions 134) (Scheme 15). (7-Bromo-5-mesyloxy)indoline reacted with (6-formyl-3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions to give the pyrrolophenanthridone ring system 128, which was reduced with sodium bis(2-methoxyethoxy)alumi-num hydride (SMEAH) in boiling toluene to produce ungeremine (48) in 54% yield. Also, starting with 7-iodoindoline, a similar reaction sequence afforded anhydrolycorin-7-one (119), which was transformed to hippadine (44) in 90% yield by oxidation with DDQ. 

---