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The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong Gram-positive and Gram-negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet–Spengler reaction, that mimics their biosynthetic pathways. Herein, we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of nonnatural analogs.

The fully regioselective reactivity of four new highly substituted silyl aryl triflate aryne precursors in aryne acyl-alkylation, acyl-alkylation/ condensation, and heteroannulation reactions is reported. The application of these more complex arynes provides access to diverse natural product scaffolds and obviates late-stage functionalization of aromatic rings.It has been well established that substituted arynes undergo nucleophilic attack with levels of regioselectivity dependent on the identity of substituents and their locations relative to the reactive aryne triple bond. 1 In our own investigations, we have observed fully regioselective acyl-alkylation 2 and aryne heteroannulation 3 reactions with the aryne (2) generated in situ from a 3-methoxy-substituted silyl aryl triflate (1) (Scheme 1). Each of these products (3-6) stems presumably from initial attack at C(1) of the aryne (2), which suggests that the o-methoxy substituent electronically polarizes the triple bond and sterically shields the adjacent atom to favor this reactivity. More recently, we have been able to exploit this selectivity in aryne acyl-alkylation/condensation sequences to produce either substituted hydroxynaphthoquinones (6) or hydroxyisoquinolines (5). 4 These observations led us to investigate whether more highly functionalized silyl aryl triflates would also exhibit the predictable regioselectivity seen for precursor 1.Specifically, we chose to examine whether unsymmetrically substituted polyalkyoxy silyl aryl triflates would react

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A catalytic method for the decarboxylative coupling of 2-(azaaryl)carboxylates with aryl halides is described. The decarboxylative cross-coupling presented is mediated by a system catalytic in both palladium and copper without requiring stoichiometric amounts of organometallic reagents or organoboronic acids. This method circumvents additional synthetic steps required to prepare 2-azaaryl organometallics and organoborates as nucleophilic coupling partners, which are prone to protodemetallation and protodeborylation and produce potentially toxic byproducts.