Synthesis of Six Membered Nitrogen Heterocycles: Boronate Mediated Functionalization of Pyridine and the Selective Synthesis of (+)-Dysoline

Nitrogen containing heterocycles play a crucial role in the discovery and development of therapeutically important compounds. As of 2014 an analysis performed by Njarðarson et al. identified that 59 % (640 out of 1086) of all FDA approved drugs contain a nitrogen heterocycle.1 Piperidine (19%, 72 FDA approved drugs) and pyridine (16.4%, 62 FDA approved drugs) represent the most abundant of these nitrogen heterocycles. Further inflating the role of N-heterocycles is their prevalence in Nature, in particular alkaloid natural products represent versatile structural motifs that have been of synthetic and therapeutic interest for decades. Discussed herein are two projects related to the preparation and study of N-heterocycles: A methodology involving boronate mediated functionalization of pyridines and the total synthesis of the chromone alkaloid (+)-dysoline. Addition of a metalated nucleophile to pyridine boroinc ester with subsequent activation propagates a 1,2 boron to carbon migration. The resulting dihydropyridine intermediate can then be subjected to a variety of conditions allowing access to the desired pyridine, dihydropyridine, tetrahydropyridine or piperidine motif. This reaction was shown to work for a variety of nucleophiles, in addition substitution of the pyridine boronic ester was well tolerated. Expansion of this method into the quinoline and isoquinoline also gave positive results albeit with more moderate yields. Dysoline, a novel chromone alkaloid isolated from Dysoxylum binectariferun, was reported to have selective cytotoxicity for HT1080 fibrosarcoma cells (IC50 of 0.21 μM). Given the scarcity of natural material a concise and selective synthesis of (+)-dysoline has been developed allowing for further biological evaluation. Construction of the C6 chromone core with complete regioselectivity was achieved with a Danheiser benzannulation. Additionally, an enantioselective nucleophile catalyzed aldol lactonization (NCAL) formed the piperidine ring with control of relative and absolute stereochemistry.