Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones

Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished.     

Highly enantioselective synthesis of rigid, quaternary 1,4-benzodiazepine-2,5-diones derived from proline

[reaction: see text] Proline-derived 1,4-benzodiazepine-2,5-diones are extremely useful scaffolds in medicinal chemistry. In this paper, we describe a protocol for retentive C3 alkylation of these materials, thus accomplishing the direct synthesis of enantiopure quaternary 1,4-benzodiazepine-2,5-diones. The high enantioselectivities (up to 99.5%) are attributed to memory of chirality.     

Imaging cytoplasmic cAMP in mouse brainstem neurons

Background  

cAMP is an ubiquitous second messenger mediating various neuronal functions, often as a consequence of increased intracellular Ca²⁺ levels. While imaging of calcium is commonly used in neuroscience applications, probing for cAMP levels has not yet been performed in living vertebrate neuronal tissue before.     

Stable isotopic studies of earthworm feeding ecology in tropical ecosystems of Puerto Rico

Feeding strategies of earthworms and their influence on soil processes are often inferred from morphological, behavioral and physiological traits. We used (13)C and (15)N natural abundance in earthworms, soils and plants to explore patterns of resource utilization by different species of earthworms in three tropical ecosystems in Puerto Rico. In a high altitude dwarf forest, native earthworms Trigaster longissimus and Estherella sp. showed less (15)N enrichment ((15)N = 3-6 per thousand) than exotic Pontoscolex corethrurus ((15)N =7-9 per thousand) indicating different food sources or stronger isotopic discrimination by the latter. Conversely, in a lower altitude tabonuco forest, Estherella sp. and P. corethrurus overlapped completely in (15)N enrichment ((15)N = 6-9 per thousand), suggesting the potential for interspecific competition for N resources. A tabonuco forest converted to pasture contained only P. corethrurus which were less enriched in (15)N than those in the forest sites, but more highly enriched in (13)C suggesting assimilation of C from the predominant C(4) grass. These results support the utility of stable isotopes to delineate resource partitioning and potential competitive interactions among earthworm species. Copyright 1999 John Wiley & Sons, Ltd.