Ever since Pasteur noticed that tartrate crystals exist in two non-superimposable forms that are mirror images of one another--as are left and right hands--the phenomenon of chirality has intrigued scientists. On the molecular level, chirality often has a profound impact on recognition and interaction events and is thus important to biochemistry and pharmacology. In chemical synthesis, much effort has been directed towards developing asymmetric synthesis strategies that yield product molecules with a significant excess of either the left-handed or right-handed enantiomer. This is usually achieved by making use of chiral auxiliaries or catalysts that influence the course of a reaction, with the enantiomeric excess (ee) of the product linearly related to the ee of the auxiliary or catalyst used. In recent years, however, an increasing number of asymmetric reactions have been documented where this relationship is nonlinear, an effect that can lead to asymmetric amplification. Theoretical models have long suggested that autocatalytic processes can result in kinetically controlled asymmetric amplification, a prediction that has now been verified experimentally and rationalized mechanistically for an autocatalytic alkylation reaction. Here we show an alternative mechanism that gives rise to asymmetric amplification based on the equilibrium solid-liquid phase behaviour of amino acids in solution. This amplification mechanism is robust and can operate in aqueous systems, making it an appealing proposition for explaining one of the most tantalizing examples of asymmetric amplification-the development of high enantiomeric excess in biomolecules from a presumably racemic prebiotic world.

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This paper describes the process development conducted toward the multi-kilogram synthesis of a hemiadipic acid pro-drug of buprenorphine. The major challenges were to control the levels of the dibuprenorphine monoadipate impurity and to improve the robustness of the final recrystallization. Modification of the reaction conditions limited the levels of the impurity formed during the reaction, and an additional point of control was introduced, a reslurry with dichloromethane. The solid-state properties of the pro-drug were fully investigated, and extensive polymorph screening was undertaken. An unusual low-temperature endothermic event was observed in the differential scanning calorimetry thermogram. This low-temperature event was further investigated using variable-temperature X-ray powder diffraction and variable-temperature solid-state nuclear magnetic resonance spectroscopy. It was concluded that this event was likely to be associated with a reversible, minor conformational change of the adipate side chain.

Various 1,3‐dimethyl and 1‐methyl‐3‐phenylfuro[3,4‐c]coumarins (5a‐h and 6a‐h) have been synthesized by demethylation cyclization of the respective 3‐aryl‐4‐ethoxycarbonyl furans (3a‐h and 4a‐h). These ethoxycarbonyl furans were prepared by reacting appropriate 1‐aryl‐2‐nitro‐prop‐1‐ene (1a‐h) with ethyl acetoacetate or ethyl benzoylacetate under Nef reaction condition.

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