Synthesis of N-acyl amide natural products using a versatile adenylating biocatalyst.

Natural products are secondary metabolites produced by many different organisms such as bacteria, fungi and plants. These biologically active molecules have been widely exploited for clinical application. Here we investigate TamA, a key enzyme from the biosynthetic pathway of tambjamine YP1, an acylated bipyrrole that is produced by the marine microorganism Pseudoalteromonas tunicata. TamA is a didomain enzyme composed of a catalytic adenylation (ANL) and an acyl carrier protein (ACP) domain that together control the fatty acid chain length of the YP1. Here we show that the TamA ANL domain alone can be used to generate a range of acyl adenylates that can be captured by a number of amines thus leading to the production of a series of fatty N-acyl amides. We exploit this biocatalytic promiscuity to produce the recently discovered class of N-acyl histidine amide natural products from Legionella pneumophila.

Post-Ugi Cascade Transformations for Accessing Diverse Chromenopyrrole Collections.

Employing a build/couple/pair strategy, a serendipitous one-pot protocol for the diastereoselective construction of diverse collections of chromenopyrroles is described. This methodology features an unprecedented five-step cascade including azomethine ylide generation followed by in situ intramolecular [3 + 2]-cycloaddition. Furthermore, this protocol was extended to access enantiopure chromenopyrroles using amino acids as chiral auxiliary. Moreover, postpairing reactions were employed to increase the diversity and complexity of our pilot compound collections.

Modular Bi-Directional One-Pot Strategies for the Diastereoselective Synthesis of Structurally Diverse Collections of Constrained ß-Carboline-Benzoxazepines.

The development of robust and efficient strategies to access structurally diverse drug-like compound collections remains an important challenge for small molecule probe development and drug discovery. Following a build/couple/pair strategy we have established bidirectional approach to unprecedented benzoxazepines by employing a Pictet-Spengler/aza-Michael addition cascade and Schiff base/aza-Michael addition/reduction protocols, respectively. The corresponding ß-carboline-fused benzoxazepines and peripherally substituted benzoxazepines are isolated in high diastereoselectivity, good to excellent yields and have, to the best of our knowledge, never been reported.