Suspended Amination

Chemists solve a 46-year- old problem to develop a new drug modification method.

When Pfizer approached Phil Baran and his colleagues at the Scripps Research Institute in the US with an urgent problem, it was only after a literature review that they appreciated the enormity of the task before them. The company was having difficulties in producing its promising cancer clinical candidate bicyclo[1.1.1]pentan-1-amine in large enough quantities for clinical trials – and it needed a direct route to kilo-scale synthesis of the drug.

Bicyclo[1.1.1]pentan-1-amine is a molecule in which carbon atoms are arranged in rings at odd angles, with relatively large bond energies. Drugs containing the ring structures are more resistant to enzymatic breakdown – potentially increasing their therapeutic potential. But adding the structures to existing drugs is difficult – so much so that chemists have had to redesign the entire synthesis around the rings – often taking multiple steps and producing very poor yields.

Baran and his colleagues figured that a direct amination across the central bond would be the best approach to solve the problem. A relatively simple solution – so simple that someone must have tried it before... And indeed, not only had several attempts been made to directly animate the precursor, but researchers had been trying for the past 46 years – to no avail.

“[1.1.1]propellane is volatile and unstable – we not only had to develop a “one-pot” procedure for its generation and reaction, but also work within numerous restrictions regarding reaction conditions, since we had to make the process amenable to large scale,” says Baran, lead author of the study and Professor of Chemistry at the Scripps Research Institute. “We were put in a tight spot.”

After numerous failed attempts to develop a direct amination reaction, the researchers were inspired by previous literature reports whereby strained bonds were broken with metalated carbon nucleophiles. They eventually managed to directly append the carbon ring structure – propellane – to the precursor molecule to produce bicyclo[1.1.1]pentan-1-amine. They called the technique a “strain-release amination” whereby amines are used to break “spring-loaded” C-C and C-N bonds in a click-like manner to install bioisosteres. “Once we discovered this method, we sought to explore strain-release as a more general approach to other ring systems that ultimately led to the development of a peptide functionalization reaction with our “designer” sulfones,” says Baran.

“This technique is exciting because it allows for “any-stage” functionalization of amines with several small ring bioisosteres which was previously difficult or impossible,” Baran says. “We are sure pharmaceutical companies will be excited to start using this method to make molecules that they have designed but haven’t been able to synthesize.”

In the paper, Baran and his colleagues includ extensive, photographical “how-to” supporting information, along with detailed procedures and troubleshooting guides. “This method should be straightforward for other chemists to use and has been extensively field tested at Pfizer,” he says, “Developing a new reaction is always exciting, but I think the most memorable moment of this project is still to come - our dream is to go from bench to bedside.”

  1. R. Gianatassio et al., “Organic chemistry. Strain-release amination,” Science, 351, 6270, 241-246 (2016). PMID: 26816372.

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