Scheme 1. Methods for the Generation of Benzyne (1) Scheme 2. Representative Reactions of Benzyne (1) 6 Review pubs.acs.org/CR

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

A general approach for the synthesis of benzannulated macrolactone natural products utilizing an aryne acyl-alkylation reaction is described. Toward this end, the total syntheses of the natural products (−)-curvularin, curvulin, and (−)-diplodialide C are reported. Furthermore, the aryne insertion technology has enabled the rapid conversion of simple diplodialide natural products to curvularin, thereby connecting these two biosynthetically distinct classes of compounds via synthetic methods.

The (salen) Co catalyst (4a) can be prepared as a mixture of cyclic oligomers in a short, chromatography-free synthesis from inexpensive, commercially available precursors. This catalyst displays remarkable enhancements in reactivity and enantioselectivity relative to monomeric and other multimeric (salen) Co catalysts in a wide variety of enantioselective epoxide ring-opening reactions. The application of catalyst 4a is illustrated in the kinetic resolution of terminal epoxides by nucleophilic ring-opening with water, phenols, and primary alcohols; the desymmetrization of meso epoxides by addition of water and carbamates; and the desymmetrization of oxetanes by intramolecular ring opening with alcohols and phenols. The favorable solubility properties of complex 4a under the catalytic conditions facilitated mechanistic studies, allowing elucidation of the basis for the beneficial effect of oligomerization. Finally, a catalyst selection guide is provided to delineate the specific advantages of oligomeric catalyst 4a relative to (salen) Co monomer 1 for each reaction class.