Directed Remote Lateral Metalation: Highly Substituted 2-Naphthols and BINOLs by In Situ Generation of a Directing Group.

A general synthesis of highly substituted 2-naphthols based on a new carbanionic reaction sequence is demonstrated. The reaction exploits the dual nature of lithium bases consisting of consecutive ring opening of readily available coumarins with either LiNEt2 or LiNiPr2 into Z-cinnamamides, thus generating a directing group in situ and allowing, by conformational freedom, a lateral directed remote metalation for ring closure to give the aryl 2-naphthols in good to excellent yields. These transformations can be combined to provide a more efficient one-pot process. Mechanistic insight into the remote lateral metalation step, demonstrating the requirement of Z-cinnamamide, is described. Application of this methodology to the synthesis of highly substituted 3,3'-diaryl BINOL ligands is also reported.

An Approach to the Core of Lactonamycin.

A cascade reaction has been developed for the synthesis of lactonamycin. In this paper, we demonstrate that a transition-metal-free thermal ene-diyne cyclization can be used for the construction of the entire core of the antibiotic lactonamycin and anticancer agent lactonamycin Z.

Synthesis of substituted imidazo[1,5-a]pyrazines via mono-, di-, and directed remote metalation strategies.

Imidazo[1,5-a]pyrazines 1 undergo regioselective C3-metalation and C5/C3-dimetalation to afford a range of functionalized derivatives 2a-2g (Table 1 ), and 4a-4d (Table 2 ). Under similar conditions, the C3-methyl derivatives 2a and 5 undergo surprising regioselective C5-deprotonation to afford, after electrophile quench, products 4b and 6a-6p (Table 3 ), results that are rationalized by quantum mechanical calculations. Benzamide 7b, obtained from such metalation chemistry followed by Suzuki cross coupling, undergoes directed remote metalation-cyclization to afford 8, representing the hitherto unknown triazadibenzo[cd,f]azulen-7(6H)-one tricyclic ring system.

A new route to highly functionalized heterocyclic rings.

A novel cascade reaction has been developed for the rapid construction of heterocyclic rings. The cyclization is thermally induced and does not involve the use of metal ions. This highly efficient construction of furans has been developed during studies directed toward the synthesis of the antibiotic lactonamycin 1.