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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.

Described is a concise total synthesis of N-methylwelwitindolinone D isonitrile, the first in a family of complex bicyclo[4.3.1]decane-containing indole alkaloids to yield to synthesis. The complete carbon core of the natural product was assembled rapidly through a Lewis acid-mediated alkylative coupling followed directly by a palladium-catalyzed enolate arylation reaction. The final ring of the pentacycle was introduced by an indole oxidation/cyclization, and the isonitrile was installed through the rearrangement of an alde-hyde to an isothiocyanate followed by desulfurization.

Described in this report is a rapid asymmetric total synthesis of the tetrahydroisoquinoline antitumor antibiotic (−)-quinocarcin. The sequence employs a mild fluoride-induced aryne annulation developed in our laboratories to build a key isoquinoline-containing intermediate comprising the entire carbon scaffold of the natural product. This intermediate is advanced through six additional steps to the target alkaloid, providing the shortest synthetic route to (−)-quinocarcin reported to date.

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A convenient method is disclosed for the synthesis of both 3-hydroxyisoquinolines and 2-hydroxy-1,4-naphthoquinones from b-ketoesters using a one-pot aryne acyl-alkylation/condensation procedure. When performed in conjunction with a one-step method for the synthesis of the b-ketoester substrates, this method provides a new route to these polyaromatic structures in only two steps from commercially available carboxylic acid starting materials. The utility of this approach is demonstrated in the synthesis of the atropisomeric P,N-ligand, QUINAP.Synthetic chemists are constantly in search of new reaction sequences to convert simple, readily available starting materials into increasingly complex products. The most useful and economically valuable of these processes are able to do so quickly and with little operational difficulty. 1 It was with this concept in mind that we designed a procedure for the conversion of b-ketoesters to either 3-hydroxyisoquinolines or 2-hydroxy-1,4-naphthoquinones using a novel one-pot aryne acyl-alkylation/condensation sequence. Furthermore, when this process is coupled with a one-step synthesis of the b-ketoester substrates, it provides an exceptionally general two-step procedure for the conversion of readily available carboxylic acids to either of these important bicyclic aromatic structures. 2 Traditional approaches to the incorporation of these aromatic functionality within larger molecular scaffolds have typicallyThe Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Boulevard, MC 164-30, Pasadena, CA 91125, USA. E-mail: stoltz@caltech.edu; Fax: +1 626 564 9297; Tel: +1 626 395 6064 † Electronic supplementary information (ESI) available: General experimental procedures, characterization data, NMR, and IR spectra. See DOI: 10.1039/b913336dScheme 1 Aryne acyl-alkylation followed by condensation with ammonia or intramolecular condensation and oxidation.relied upon transition metal-catalyzed cross coupling reactions employing C(sp 2 )-X precursors. 3 As an alternative to this strategy, we have been exploring methods to prepare various heteroaromatic systems via condensation of arynes with derivatives of carboxylic acids. 4 Following our report of a fluoride-induced insertion reaction between b-ketoesters (1) and arynes derived from silyl aryl triflates (2), 5 we began to investigate avenues by which the acyl-alkylated arene products (3) could be advanced toward larger ring systems (Scheme 1). 6 Our interest in nitrogencontaining heterocycles 7 led us to a report by Bentley et al., in which the synthesis of both 3-hydroxyisoquinolines (4) and 2-hydroxy-1,4-naphthoquinones (5) is accomplished by exposure of 1,5-ketoesters similar to 3 to either aqueous ammonia or alkaline base under an ambient atmosphere, respectively. 8 Indeed, we found that treatment of a crude acyl-alkylation reaction mixture containing methyl (2-acetylphenyl)acetate (3) with aqueous ammonium hydroxi...

As part of a comprehensive strategy to the welwitindolinone alkaloids possessing a bicyclo[4.3.1]decane core, we report herein concise asymmetric total syntheses of (−)-N-methylwelwitindolinone C isothiocyanate (2a), (−)-N-methylwelwitindolinone C isonitrile (2b), and (−)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate (3a) from a common tetracyclic intermediate. The crucial vinyl chloride moiety was installed through electrophilic chlorination of a hydrazone, but only after adjustment of reactivity to circumvent a facile skeletal rearrangement. Selective desulfurization and oxidation of 2a provided access to 2b and 3a, respectively. Notably, this work provides corrected 1H and 13C NMR spectral data for 3a.

Detection of iBCVI has become a common clinical conundrum with improved and routine imaging. Indeterminate BCVI is not completely benign, with 25.4% demonstrating anatomical progression to true BCVI and 5.1% developing cerebrovascular symptoms. We therefore recommend serial imaging and antiplatelet therapy for iBCVI.