Discovery of dual positive allosteric modulators (PAMs) of the metabotropic glutamate 2 receptor and CysLT1 antagonists for treating migraine headache.

Pyridylmethylsulfonamide series were the first reported example of positive allosteric modulators (PAM) of the mGlu2 receptor. The hydroxyacetophenone scaffold is a second series of mGlu2 PAMs we have identified. This series of molecules are potent mGlu2 potentiators and possess significant CysLT1 (cysteinyl leukotriene receptor 1) antagonist activity, showing in vivo efficacy in a dural plasma protein extravasation (PPE) model of migraine. In this paper, we describe the dual SAR, pharmacokinetics and preclinical in vivo efficacy data for a tetrazole containing hydroxyacetophenone scaffold.

Catalyst and ring size effects on periselectivity of oxonium ylide rearrangements.

Diazoketones were subjected to carbene-transfer with Rh(II) or Cu(II) catalysts to probe the selectivity for rearrangement via five- or six-membered oxonium ylides. 4,5-Bis(benzyloxy) and 4-allyloxy-5-benzyloxy substrates 3a,b showed a large preference for rearrangement via the five-membered ylide under all conditions. However, a sharp divergence was seen with 5-allyloxy-4-benzyloxy substrate 3c, which underwent predominantly a [2,3]-shift to pyran 5c via the six-membered ylide with Cu(II) catalysis and a [1,2]-shift to furan 4c via the five-membered ylide with Rh(II) catalysis.

Cyclooctanoid ring systems from mixed acetals via heteroatom-assisted [1,2]-shift of oxonium ylides.

Cyclic mixed acetals with pendant diazoketone side chains undergo efficient rearrangement to ether-bridged cyclooctanoid systems upon treatment with Cu(hfacac)2. This result demonstrates that heterosubstituted carbons are suitable migrating groups for the Stevens [1,2]-shift of oxonium ylides. In the case of a mixed thioacetal, the resulting sulfide served as a trigger for cleavage of the bridging ether through one of two complementary strategies, furnishing a bicyclo[6.3.0]octene product with an angular hydroxyl group.

New efficient iterative approaches to polycyclic ethers.

The imposing structures of the marine polyether ladder toxins have inspired synthetic chemists to develop many clever methods for assembling these complex skeletons. One intriguing strategy is to use a short and reliable sequence of reactions to build successive rings in an iterative fashion. The ideal approach should tolerate variation in ring size and substitution at the bridgehead positions. This paper offers an overview of recent progress in this field.