VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate.

This letter describes progress towards an M4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the ß-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe.

Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents.

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.

Enantioselective synthesis of metacycloprodigiosin via the "Wasserman pyrrole".

A concise, nine-step enantioselective total synthesis of metacycloprodigiosin is reported. The synthesis provides increased step-efficiency over the previous racemic and enantioselective syntheses of this compound. Key features of the work include investigations into a convergent oxidative coupling reaction and subsequent ring-closing metathesis to deliver an advanced pyrrole intermediate we name the "Wasserman pyrrole" that can be converted to metacycloprodigiosin in one step.

Spiroaminal Model Systems of the Marineosins with Final Step Pyrrole Incorporation.

In this Letter, we describe a short, 6-step enantioselective route to spiroaminal lactam model systems reminiscent of marineosins A and B has been developed starting from either (R)- or (S)-hydroxysuccinic acid, respectively, in ~9% overall yield. This route enables late stage incorporation of the pyrrole ring at C5 via nucleophilic displacement of an iminium triflate salt.

A General, Enantioselective Synthesis of 1-Azabicyclo[m.n.0]alkane Ring Systems.

In this Letter, we describe a novel approach for the general and enantioselective synthesis of a diverse array of small to large 1-azabicyclo[m.n.0]alkyl ring systems with an embedded olefin handle for further functionalization. The stereochemistry is established via a highly diastereoselective indium-mediated allylation of an Ellman sulfinimine in greater than 9:1 dr., which is readily separable by column chromatography to afford a single diastereomer. This methodology allows for the rapid preparation of 1-azabicyclo[m.n.0]alkane ring systems that are not readily accessible through any other chemistry in excellent overall yields and, for many systems, the only enantioselective preparation reported to date.

Towards the Total Synthesis of Marineosin A: Construction of the Macrocyclic Pyrrole and an Advanced, Functionalized Spiroaminal Model.

Herein, we describe the enantioselective construction of the 12-membered macrocyclic pyrrole core 4 of marineosin A in 5.1% overall yield from (S)-propylene oxide. The route features a key Stetter reaction to install a 1,4-diketone, which is then subjected to Paal-Knorr pyrrole synthesis and ring closing metathesis (RCM) to afford macrocycle 4. A divergence point in the synthetic scheme also enabled access to a highly functionalized spiroaminal model system 8 via an acid-mediated hydroxyketoamide cyclization strategy.

Enantioselective total synthesis and studies into the configurational stability of bismurrayaquinone A.

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.

Enantioselective synthesis of biphenols from 1,4-diketones by traceless central-to-axial chirality exchange.

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 BF(3)·OEt(2). On the basis of X-ray crystallographic data, a stereochemical model for this chirality exchange process is put forth.

Oxidative carbon-carbon bond formation via allyldimethylsilyl enol ethers.

A method for the oxidative alkylation of ketones through intramolecular allyl-group transfer within preformed allyldimethylsilyl enol ethers is reported. A number of examples are detailed, including a study into the effects of resident sterocenters within cyclic enol ethers.

Diastereoselective oxidative carbon-carbon bond formation via silyl bis-enol ethers.

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.