Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

A method for the enantioselective synthesis of biphenols from readily prepared 1,4-diketones is reported. Key to the success of this method is the highly selective transfer of central to axial chirality during a double aromatization event triggered by BF3•OEt2. Based upon X-ray crystallographic data, a stereochemical model for this chirality exchange process is put forth.

Diisopropylsilyl bis-enol ethers are shown to be powerful intermediates for the diastereoselective dimerization and cross-coupling of cyclic ketones. The trends observed for the oxidative coupling of a range of different dialkylsilyl bis-enol ethers derived from cyclohexanone are rationalized by invoking a stereochemical model based on a Thorpe-Ingold effect.

Lost in rotation: The concise strategy of the first enantioselective total synthesis of bismurrayaquinone A utilized traceless stereochemical exchange to form an enantioenriched biphenyl core that was elaborated in a bidirectional manner to the natural product. Observed racemization on an unsuccessful initial route prompted studies into the configurational stability of bismurrayaquinone A and related biquinones.

The carbazole alkaloids represent a large and structurally rich family of natural products that are produced by a variety of terrestrial plants. [1] In particular, plants within the Rutaceae family are notable producers of these compounds-with the genus Murraya providing the greatest number of unique structures. Commonly found in the outer Himalayas and on the Indian peninsula, the leaves of M. koenigii (L.) Spreng are, inter alia, extensively utilized as a spice flavoring by the peoples of these areas giving it the name "curry-leaf tree". Extracts of the plant are also used in local medicine due to their antimicrobial activity. [2] Within this large family of alkaloids, we were particularly interested in the axially chiral dimeric carbazoles, [3] and most specifically bismurrayaquinone A (1, Figure 1). This unique dimeric carbazolequinone was isolated from the roots of M. koenigii (L.) Spreng by Furukawa and coworkers in 1993 [4] and has been the subject of non-stereoselective total syntheses by the groups of both Bringmann and Murphy. [5] Somewhat surprisingly, there has never been an enantioselective synthesis of 1. Bringmann and coworkers did, however, prepare racemic 1 and separated the two enantiomers using preparative HPLC, [5a] and in 2001 reported an approach towards a stereoselective synthesis. [6] Because no enantioselective synthesis of bismurrayaquinone A (1) had been reported, and because there is very little literature data on axially chiral biquinones, [7] we were compelled to explore strategies for the enantioselective synthesis of these molecules. Recently, we reported the development of a new method for synthesizing enantiomerically pure axially chiral biphenols by a method we termed "traceless stereochemical exchange". [8] This method allows ready access to biphenols of the type represented by structure 2 (Figure 1), and herein we report the use of this method to conduct the first enantioselective synthesis of bismurrayaquinone A (1). These studies have also revealed a fascinating phenomenon related to the configurational stability of chiral biquinones.Our synthesis of bismurrayaquinone A (1) commenced from commercially available 4-methoxyphenol (3), which was converted into enone 4 following oxidation to the corresponding dimethylketal quinone [9] and subsequent enantioselective conjugate addition of dimethylzinc (Scheme 1). [10] ** This work was supported by the National Institutes of Health (1R01GM085322), Northwestern University (NU) and Amgen. The efficiency of the Feringa conjugate addition in terms of yield dropped from 52% on a 5 gram scale to 45% yield when conducted on 10 grams, but the enantioselectivity was maintained at 99% ee. Gram-scale oxidative dimerization of 4 was conducted under our reported conditions [8] to provide dione 5 in 63% yield (99% ee). [11] Conversion of dione 5 to bromophenol 6 proceeded smoothly after aromatization to 2 (not shown) and regioselective bromination. Our plan at this juncture was to utilize methods for palladiumcatalyzed carbazolequinone synthes...