We saw in the previous chapter how Otto Wallach’s early proposal regarding the structural origin of terpenoid natural products was later refined by the insightful work of Leopold Rudzicka, leading to the biogenetic isoprene rule and all that it implies. In a nearly parallel fashion, we find in our present chapter a second, unrelated class of naturally occurring compounds whose characteristic structural features prompted an initial innovative hypothesis by J. N. Collie near the turn of the 20th century. Collie proposed that certain natural compounds might arise from precursors containing repeated “ketide” (–CH2CO–) units which could then undergo subsequent condensations and other reactions typical of carbonyl compounds to produce some of the observed structures. Unfortunately, Collie’s work was more or less ignored and largely forgotten for nearly a half century, only to be reimagined and expanded in the middle of the century by A. J. Birch, another pioneer whose proposals met with considerable initial resistance. But unlike his predecessor, Birch ultimately prevailed by providing experimental results that supported a comprehensive theory of the biochemical origin of the group of compounds now universally known as “polyketide” natural products. This structurally diverse family includes some of the most useful medicinal agents now known to us, with many members possessing powerful antibacterial, antifungal, anticancer, immunosuppressant, and even cholesterol-lowering biological properties. As we see in Fig. 5.1, such structures range from the relatively simple to the exceedingly complex and may include large macrocyclic lactone rings (macrolides) such as erythromycin, polycyclic ethers such as monensin A, polycyclic structures which may be partly or mostly aromatic as in tetracycline, griseofulvin, or daunorubicin, or nonaromatic polycyclics such as tacrolimus and lovastatin. Some also contain noncyclic linear components that may be saturated, oxygenated, or unsaturated, as seen in different regions of amphotericin B which, like erythromycin, daunorubicin, and many other polyketides, also possesses an aglycone core which has been glycosylated with a carbohydrate component at a specific position. But in spite of this range of structures, many polyketide compounds share some common features that ultimately become more evident upon closer inspection; six-membered rings (either aromatic or nonaromatic) and multiple oxygens which tend to appear in a repeating 1,3-relationship to one another on both acyclic, cyclic, and aromatic structures.