Further advances in a practical route to tetracycline antibiotics

US scientists have synthesised by a new route a key intermediate for the production of synthetic analogues of natural antibiotic tetracyclines that could be used as potential new drugs to combat the growing ranks of antibiotic resistant bacteria. 

Andrew Myers and coworkers from Harvard University, Massachusetts, have developed a scalable five step route to an enone intermediate, which can be converted to a range of tetracyclines in three steps. The products are also crystalline at many stages, so there’s no need for purification by chromatography. 

The team made the enone by coupling a cyclohexenone with an ester - two inexpensive starting materials made in a few steps from simple precursors. ’We’ve reduced the problem of tetracycline synthesis to the synthesis of the enone, because from that molecule, you can make completely new tetracyclines,’ says Myers. ’All tetracyclines that have been approved as drugs in the last 60 years have been made by semi-synthesis - in which fermentation products are used as starting materials - and chemists’ ability to modify these natural products has been limited. We wanted to see if we could develop a completely synthetic route.’ 


The enone intermediate, a precursor to tetracyclines, was made in five steps by coupling a cyclohexenone with an ester

Myers can now make tetracyclines with modifications all around the structure’s periphery and even in the interior portion. The reaction that transforms the enone into thousands of antibiotics is a Michael-Claisen cyclisation on the left side of the enone, he explains. But it’s also possible to use a similar transformation to modify the right side. ’Because we’ve got a de novo construction of the enone, we can modify portions of the enone and greatly expand the number of new tetracyclines we can make. In fact, if you think about it, you realise it’s a multiplicative expansion because the expansions on the right side can be coupled with those on the left,’ explains Myers . 

’Myers’ chemistry has given access to novel tetracyclines that you could never make by semi-synthetic tinkering of the known natural products. And these molecules are important because they show activity against bacteria that have become resistant to the natural products,’ says Erik Sorensen, a natural products synthesis expert from Princeton University, US. ’I am hopeful that others will get involved with the problem of using synthesis to increase structural diversity within families of antibiotics because the problem of resistance in bacteria is so serious and it’s getting worse.’ 

Over the past 15 years, close to 3000 fully synthetic tetracyclines have been prepared using Myers’ route, the majority of these at Tetraphase Pharmaceuticals, of which he is the principal scientific founder. One of the compounds is about to enter phase II clinical trials for intraabdominal infections. 

Elinor Richards 

Link to journal article

A practical, convergent route to the key precursor to the tetracycline antibioticsDavid A. Kummer, Derun Li, Amelie Dion and Andrew G. Myers,?Chem. Sci., 2011, 2, 1710DOI:10.1039/c1sc00303h