Radical Retrosynthesis

Conspectus In The Logic of Chemical Synthesis, E. J. Corey stated that the key to retrosynthetic analysis was a “wise choice of appropriate simplifying transforms” ( Corey, E. J. ; Cheng, X.-M. The Logic of Chemical Synthesis; John Wiley: New York, 1989 ). Through the lens of “ideality”, chemists can identify opportunities that can lead to more practical, scalable, and sustainable synthesis. The percent ideality of a synthesis is defined as [(no. of construction rxns) + (no. of strategic redox rxns)]/(total no. of steps) × 100. A direct consequence of designing “wise” or “ideal” plans is that new transformations often need invention. For example, if functional group interconversions are to be avoided, one is faced with the prospect of directly functionalizing C–H bonds ( Gutekunst, W. R. ; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976 ; Brückl, T. ; et al. Acc. Chem. Res. 2012, 45, 826 ). If protecting groups are minimized, methods testing the limits of chemoselectivity require invention ( Baran, P. S. ; et al. Nature 2007, 446, 404 ; Young, I. S. ; Baran, P. S. Nat. Chem. 2009, 1, 193 ). Finally, if extraneous redox manipulations are to be eliminated, methods directly generating key skeletal bonds result ( Burns, N. Z. ; et al. Angew. Chem., Int. Ed. 2009, 48, 2854 ). Such analyses applied to total synthesis have seen an explosion of interest in recent years. Thus, it is the interplay of aspirational strategic demands with the limits of available methods that can influence and inspire ingenuity. E. J. Corey’s sage advice holds true when endeavoring in complex molecule synthesis, but together with the tenets of the “ideal” synthesis, avoiding concession steps leads to the most strategically and tactically optimal route ( Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97, 5784 ; Gaich, T. ; Baran, P. S. J. Org. Chem. 2010, 75, 4657 ). Polar disconnections are intuitive and underlie much of retrosynthetic logic. Undergraduates exposed to multistep synthesis are often taught to assemble organic molecules through the combination of positively and negatively charged synthons because, after all, opposites attract. Indeed, the most employed two-electron C–C bond forming reactions today are those based upon either classical cross-coupling reactions (e.g., Suzuki, Negishi, or Heck) or polar additions (aldol, Michael, or Grignard). These reactions are the mainstay of modern synthesis and have revolutionized the way molecules are constructed due to their robust and predic