ACS Meeting News: Reagent Assembles Ring Motifs Common In Drugs

Saturated heterocycles such as piperidines and morpholines are common in bioactive molecules, so drugmakers would like to have straightforward ways to incorporate them into their molecular collections. However, these rings tend to be difficult to append to molecular scaffolds, requiring laborious multistep protocols in many cases.

In contrast, chemists snap aromatic rings together with ease using metal-catalyzed cross-coupling reactions. Researchers have attempted to develop cross-couplings that work on saturated heterocycles, but they aren’t yet broadly applicable.

At the American Chemical Society national meeting in Dallas, a chemist in Jeffrey W. Bode’s lab at ETH Zurich described her entry into the fray. Although not a cross-coupling reaction per se, the reaction yields cross-coupling-type products in one step.

Bode’s team had developed a radical-mediated reaction that builds saturated heterocycles from aldehyde starting materials. The stoichiometric (noncatalytic) approach leads to six-, seven-, eight-, and nine-membered nitrogen heterocycles linked to various aromatic and nonaromatic scaffolds (Nat. Chem. 2014, DOI: 10.1038/nchem.1878; Angew. Chem. Int. Ed. 2013, DOI: 10.1002/anie.201208064; and Org. Lett. 2014, DOI: 10.1021/ol500210z).

Cam-Van T. Vo, the graduate student who presented the work in the Division of Organic Chemistry, developed air- and moisture-stable liquids she dubbed “SnAP reagents” to react with aldehydes. SnAP stands for “Tin (Sn) amine protocol” because the reagents contain tributyltin and amine groups. Vo and Bode think the tin works together with a copper additive to form a carbon radical, facilitating formation of a heterocyclic ring.

Tin’s toxicity tends to make it a nonstarter in industry circles. But Bode urges chemists to focus on the method’s useful products for now. “We believe we can eventually replace the tin, and we’re well on our way to developing versions that are catalytic in copper,” he told C&EN.

Christopher M. Adams, a senior investigator in global discovery chemistry at Novartis Institutes for BioMedical Research, has used SnAP reagents to synthesize substituted piperazines and diazepanes. The chemistry can access challenging substitution patterns with ease, he notes, justifying the use of tin reagents. “This approach should find wide application in medicinal chemistry programs,” he said.