Total synthesis and drug pursuits: the good, the bad, and the ugly

Synthetically speaking, the complex multifunctionalized environments of natural products typically limit the effectiveness of a chosen method to achieve a desired reaction. Carbanions, organometalics and counteractions, for example, will often experience competing interactions outside their designed or known roles. In a total synthesis or a chemical biology setting, each chosen method may be scrutinized on the basis of several interrelated criteria. Such ideals need to be sensibly balanced within a multistep synthesis; whether a key building block is being constructed or a key coupling step is being optimized (or even devised). Herein, we present key methods and strategies that were advanced en route to uncovering the chemistry and biology of the (1) laetirobins, (2) lipstatins, (3) platensimycins, and (4) bielschowskysin