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...
Two syntheses of 3-substituted-4-amino-[3,2-c]thienopyridines have been developed to replace the standard literature route to these compounds, which uses unattractive conditions involving azide and high temperatures. The first synthesis utilizes a Friedel-Crafts reaction as its key ring-forming step, whereas the second route relies on an unprecedented intramolecular reductive cyclization between a nitroolefin and a nitrile as its key ring-forming step. The development and optimization of each 3-substituted-4-amino-[3,2-c]thienopyridine synthesis is discussed and a comparison of the routes is presented.
Fused pyridine derivatives R 0450 Improved Synthesis of 3-Substituted-4-amino-[3,2-c]-thienopyridines. -Two new methods to prepare biologically important title heterocycles are developed. -(ENGSTROM*, K. M.; BAIZE, A. L.; FRANCZYK, T. S.; KALLEMEYN, J. M.; MULHERN, M. M.; RICKERT, R. C.; WAGAW, S.; J.
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