Cubane is a frequently discussed and highly coveted top chemistry meme molecule. This interdisciplinary video showcases the synthesis and application of cubanes in medicinal chemistry by presenting research work from MacMillan and coworkers. Given their proofofconcept on the cystic fibrosis drug Lumacaftor, we also walk through a highlevel primer on cystic fibrosis disease landscape and current treatments.

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00:00 Cube time
01:23 Refresh on BCP, cubane and COT isosteres
02:51 MacMillan's work: 1,3 disubstituted cubanes
04:55 1,2 disubstituted cubanes
05:57 Photoredox/crosscoupling with Copper
07:33 CubaLumacaftor synthesis and properties
09:48 Cystic fibrosis (CF) primer incl. treatments (most notably, Orkambi and Trikafta)
12:58 Financials
15:05 Unexpected appearance by deuterium

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Key references:
Cubanes in Medicinal Chemistry: J. Med. Chem. 2019, 62, 1078
General Access to Cubanes as Benzene Bioisosteres: Nature 2023; https://doi.org/10.1038/s4158602306... / ChemRxiv: https://chemrxiv.org/engage/apigatew...
Cyclooctatetraene: A Bioactive Cubane Paradigm Complement: Chemistry. 2019, 25, 2729
1,2Difunctionalized bicyclo[1.1.1]pentanes:Long–soughtafter mimetics forortho/metasubstituted arenes: PNAS 2021, 118, e2108881118
An example for BCP: Application of the Bicyclo[1.1.1]pentane Motif as a Nonclassical Phenyl Ring Bioisostere in the Design of a Potent and Orally Active γSecretase Inhibitor: J. Med. Chem. 2012, 55, 3414

Some recommended books on organic synthesis:
Clayden, Greeves, Warren; Organic Chemistry (basic organic chemistry knowledge)
Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (extensive toolkit of functional group reactions and applications thereof with common conditions)
Nicolaou; Classics in Total Synthesis 13 (the ultimate total synthesis trilogy)
Nicolaou; Molecules That Changed the World (the world's most important molecules and their impact on everyday life)
Carreira, Kvaerno; Classics in Stereoselective Synthesis (compilation of the groundbreaking methods of stereoselective synthesis and application to synthesis of stereochemically complex structures)