Masked acyl cyanide (MAC) reagents are shown to be effective umpolung synthons for enantioselective Michael addition to substituted enones. The reactions are catalyzed by chiral squaramides and afford adducts in high yields (90–99%) and with excellent enantioselectivities (85–98%). The addition products are unmasked to produce dicyanohydrins that, upon treatment with a variety of nucleophiles, provide γ-keto acids, esters, and amides. The use of this umpolung synthon has enabled, in enantiomerically enriched form, the first total synthesis of the prenylated polyphenol (+)-fornicin C.

Flavanones, chromanones, and related structures are privileged natural products that display a wide variety of biological activities. Although flavanoids are abundant in nature, there are a limited number of available general and efficient synthetic methods for accessing molecules of this class in a stereoselective manner. Their structurally simple architectures belie the difficulties involved in installation and maintenance of the stereogenic configuration at the C2 position, which can be sensitive and can undergo epimerization under mildly acidic, basic, and thermal reaction conditions. This review presents the methods currently used to access these related structures. The synthetic methods include manipulation of the flavone/flavanone core, carbon-carbon bond formation, and carbon–heteroatom bond formation.

We report the intermolecular palladium-catalyzed reaction of tert-butyl propargyl carbonate with tryptamine derivatives or other indole-containing bis-nucleophiles. The reaction proceeds under mild conditions and with low catalyst loadings to afford novel spiroindolenine products in good to high yields.

Increased cancer cell motility constitutes a root cause of end organ destruction and mortality, but its complex regulation represents a barrier to precision targeting. We use the unique characteristics of small molecules to probe and selectively modulate cell motility. By coupling efficient chemical synthesis routes to multiple upfront in parallel phenotypic screens, we identify that KBU2046 inhibits cell motility and cell invasion in vitro. Across three different murine models of human prostate and breast cancer, KBU2046 inhibits metastasis, decreases bone destruction, and prolongs survival at nanomolar blood concentrations after oral administration. Comprehensive molecular, cellular and systemic-level assays all support a high level of selectivity. KBU2046 binds chaperone heterocomplexes, selectively alters binding of client proteins that regulate motility, and lacks all the hallmarks of classical chaperone inhibitors, including toxicity. We identify a unique cell motility regulatory mechanism and synthesize a targeted therapeutic, providing a platform to pursue studies in humans.

The asymmetric alkylation of isoflavanones and protected 3-phenyl-2,3-dihydroquinolin-4(1H)-ones catalyzed by a novel cinchonidine-derived phase transfer catalyst E is reported. This functionalization occurs at the non-activated C3 methine to afford novel products that can easily be functionalized to generate more complex fused ring systems. The process accommodates a variety of isoflavanones and activated electrophiles and installs a stereogenic quaternary center in high yield and with goodto-excellent selectivity.Isoflavanones (3-aryl-chroman-4-ones) are a privileged class of natural products with a broad spectrum of biological activities including insecticidal, antimicrobial, antibacterial, estrogenic, antitumor, and anti-HIV activity. 1 Isoflavanones are also precursors for more complex natural products such as pterocarpans and rotenones. 1 Given their therapeutic promise, selective strategies to access new classes of isoflavanones and related structures has high value. 2 The functionalization of the C3 position could promote beneficial interactions with biological targets of interest. Specifically, an alkylation at C3 can rapidly access new members of the general class of biologically active homoisoflavanones. 3 The installation of stereodefined quaternary centers 4 in aryl-substituted indanones has been reported 5 but the corresponding methodology for the related isoflavanones has not be developed to the same extent. The larger core structure of isoflavanones (six carbons versus five for indanones) and potential scission of the C-O bond via elimination under basic conditions make modifications at C3 with established approaches a challenging endeavor. The palladium-catalyzed asymmetric alkylations of enol carbonates developed independently by Stoltz and Trost is restricted to allyl electrophiles and related structures by virtue of the reaction mechanism. 6 Alkylations of aryl ketones with a strongly electron-withdrawing group (F, CO 2 R, CN) in the α-position have recently been reported separately by Deng, Dixon and Jorgensen using phase transfer catalysis (PTC). 7 Transition metal-catalyzed enantioselective α-arylations of tetralones and indanones have also been reported, but surprisingly, these reactions have focused predominately on α-methyl substituted substrates. 8 To date, a general solution to produce C3-substituted isoflavanones efficiently with high enantiomeric excess for the newly formed quaternary stereogenic center has not emerged. We report herein the direct scheidt@northwestern.edu. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 September 3. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript asymmetric alkylation of isoflavanones (1, Y=O) and protected 3-phenyl-2,3-dihydroquinolinones (1, Y=NP) catalyzed by a new cinchonidine-derived quaternary ammonium salt to afford alkylated heterocycles (2, eq. 1).Our studies began by treating isoflavanone (1a) with allyl bromide and surveying various cinchonidine-derived quaterna...