The document discusses several challenges for the industrial synthesis of complex molecules, including the need for stereocontrol, control of reactivity, and purification. It notes the importance of avoiding extreme reaction conditions and problematic reagents while making a synthesis scalable. The document also lists several researchers working on synthetic studies and includes quotes about practice versus theory and the nature of particles.

1. • Complex molecules can be industrial targets • General 20 step rule for industrial synthesis does not apply • Defining “scale” • Heathcock estimates only a few grams needed for full clinical • A number of synthetic challenges present

2. • Tremendous need to stereocontrol • Tremendous need to control reactivity • Highly substituted tetrahydropyran rings • Spiroketal orientation

3. Easy isolation and purification • Recrystalization, unreactive by-products • Avoid chromatographic separations • Recovery of material • Starting material, reagents • Avoid extreme reaction conditions • High pressure, cryogenic • Avoid problematic reagents • Pyrophoric, toxic, environmentally unfriendly Making a Synthesis Amenable to Scale-Up

4. “ A molecule that paved my way to postdoc by various modes of cyclizations and has gotten me publications.”

5. Synthetic Studies Overman,L. University of California, Irvine Romo, D. TAMU college station Austin, D. J. Yale Harran, P. SWMED, Dallas, Tx Chen, C. SWMED, Dallas, Tx Carreira, E. ETH Switzerland Baran, P. S Scripps Institute Gleason, J. McGill, Canada Horne, D Oregon state university Lindel, T LM University, Germany Shair, M Harvard Sorensen, E Princeton Williams , R Colorado State University Ali A ICSN-France GIN, D. Y MSKCC DuBois, J Stanford University

6. Law of Threes: It always takes three times to do anything right. The first time you either overshoot or undershoot; the second time you either over-compensate or under-compensate; it's not until the third time that you have a chance to get it right.