Synthesis and SAR of novel GPR39 agonists and positive allosteric modulators.

We report a significant decrease in transcription of the G protein-coupled receptor GPR39 in striatal neurons of Parkinson's disease patients compared to healthy controls, suggesting that a positive modulator of GPR39 may beneficially impact neuroprotection. To test this notion, we developed various structurally diverse tool molecules. While we elaborated on previously reported starting points, we also performed an in silico screen which led to completely novel pharmacophores. In vitro studies indicated that GPR39 agonism does not have a profound effect on neuroprotection.

Assembly-line synthesis of organic molecules with tailored shapes.

Molecular 'assembly lines', in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon-boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes-helical or linear-depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required.

Synthesis of dimethyl sulfomycinamate.

[reaction: see text] Dimethyl sulfomycinamate, the oxazole-thiazole-pyridine product generated in the methanolysis of the thiopeptide antibiotic sulfomycin I, is prepared in 13 steps and 8% overall yield by the Bohlmann-Rahtz heteroannulation of 1-(oxazol-4-yl)enamines and methyl 4-(trimethylsilyl)-2-oxobut-3-ynoate.

A new one-pot three-component condensation reaction for the synthesis of 2,3,4,6-tetrasubstituted pyridines.

The one-pot three-component condensation of a beta-ketoester, ammonia and an alkynone in the presence of a Brønsted or Lewis acid or Amberlyst 15 ion exchange resin provided 2,3,6-trisubstituted or 2,3,4,6-tetrasubstituted pyridines directly in good yield and with total regiocontrol.

First synthesis of an amythiamicin pyridine cluster.

The pyridine-containing central domain of the amythiamicin group of thiopeptide antibiotics is prepared in protected form in 9 steps, 93%ee and 18% overall yield from (S)-2-[1-(tert-butoxycarbonylamino)-2-methylpropyl]thiazole-4-carboxylic acid by Michael addition-cyclodehydration of a 2-(2-thiazolyl)enamine and 1-(2-thiazolyl)propynone.

One-pot multistep Bohlmann-Rahtz heteroannulation reactions: synthesis of dimethyl sulfomycinamate.

[reaction: see text] The synthesis of dimethyl sulfomycinamate, the acidic methanolysis product of the sulfomycin family of thiopeptide antibiotics, from methyl 2-oxo-4-(trimethylsilyl)but-3-ynoate is achieved in a 2,3,6-trisubstituted pyridine synthesis that proceeds with total regiocontrol in 13 steps by the Bohlmann-Rahtz heteroannulation of a 1-(oxazol-4-yl)enamine or in 12 steps and 9% yield by three-component cyclocondensation with N-[3-oxo-3-(oxazol-4-yl)propanoyl]serine and ammonia in ethanol.

A facile solution phase combinatorial synthesis of tetrasubstituted pyridines using the Bohlmann-Rahtz heteroannulation reaction.

The solution phase combinatorial Bohlmann-Rahtz reaction gives highly functionalized pyridine libraries from enamino esters and alkynones in a single synthetic step. Good product ratios and library purities were obtained in reactions catalyzed by zinc(II) bromide, the acid-catalyzed heteroannulation procedure offering considerable improvements over traditional methodology.