Guest Post: The Medicinal Chemistry Reaction Cookbook- Packards and DeLoreans
May10

Guest Post: The Medicinal Chemistry Reaction Cookbook- Packards and DeLoreans

We'd like to welcome the talented SeeArrOh to The Haystack as a guest blogger. A Ph.D. chemist working in industry, you might recognize SeeArrOh from the comment threads of your favorite pharma blogs, from Twitter, or from a recent Chemjobber guest post. SAO also enjoyed the paper on what medicinal chemists actually make that caught Derek Lowe's eye yesterday. You'll notice a few similar ideas to Derek's in SAO's commentary, but a few different insights as well. Every so often, it comes up: Is there anything really new in med-chem? Is everything just a re-hash of time-honored reactions, set up with closed eyes to produce yellow oils and white solids? Or are there untapped territories ripe for exploration? Sadly, Doc Brown can’t pull up in his fusion-powered DeLorean to tell us what cancer-curing medicines await us in fifty years, so we went to the literature instead. As authors of a recent J. Med. Chem ASAP (DOI: 10.1021/jm200187y) muse: …discussions with other chemists have revealed that many of our drug discovery colleagues outside the synthetic community perceive our syntheses…[are] predominantly composed of amine deprotections to facilitate amide formation reactions, and Suzuki couplings to produce biaryl derivatives. These “typical” syntheses invariably result in large, flat, achiral derivatives, destined for screening cascades. Our intrepid British authors Roughley and Jordan - his full name, Allen Michael Jordan, was enough to entice this reader - make a case for a wide variety of possible molecular manipulation. Focusing on the output of three med-chem titans: GSK, Pfizer, and AstraZeneca, and papers from three high-impact journals (JMC, BMC, BMCL), they crunch the numbers on drug discovery synthesis and reveal some expected—and unexpected—results. Given the limited scope, the authors admit right away that their findings might not be comprehensive. But hey, let’s dive into the data anyway! As a bench chemist, I’ve run my fair share of metal-catalyzed couplings, salt formations, and acetylations, so I fully expected total domination of the list by these “workhorse” reactions. Was I right? In all, the authors analyzed 7,000 different reactions, and considered some 3,600 final compounds. Perhaps most surprising, given the recent Nobel prize given out for the mighty palladium catalysts, the C-C bond-forming reactions uncovered represented only ~10% of the total! Roughly 20% of the reactions covered are “tricks of the trade” - protecting group strategies used by chemists to deactivate or cap an otherwise reactive group of atoms. Further, half of the reactions analyzed actually couple carbon to other elements such as nitrogen, sulfur, or oxygen, so-called “C-X formation”. Only 1.5% of these reactions were oxidations, while four times as many reductions were reported. The authors speculate that...

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