1. Total Synthesis of (+) Plicamine Bryan Klebon May 8, 2012 Ley et al, ACIE (2002) 41, 2194

2. Steven Ley BP Professor of Organic Chemistry, University of Cambridge Completed over 130 netural product synthesises In 2011, included in The Times list of 100 most important people in British science Pioneered use of immobilized reagents in synthesis President of RSC 2000-2002 1

3. (+) Plicamine 1999: Isolated from Crinum bulbispermum, a herbaceous plant native to South Africa Used by Zulu, Sotho and Tswana people to treat rheumatism, aching joints, septic sores, varicose veins and kidney and bladder infections 2

4. Solid supported reagents Benefits –Easily use excess of reagent to drive reaction to completion –Combination of traditionally incompatible reagents for novel cascade reactivity –Recovery and reuse of reagents –Simplify purification 3

5. Retrosynthesis 4 +

6. 1)TMSCl, MeOH 2) 3) NH 2 Me, MeOH Synthesis of 17 5 1) 2) 20 19 24 Tf 2 O, PVP, poly-DMAP PVP Poly-DMAP 17 100% 91% from 19

7. Phenolic Oxidative Coupling 6 17 16 CF 3 CH 2 OH 82%

8. 7 16 15 100% 28

9. 8 TMSCHN 2 95% 29 31 Microwave, 100C 20 min 96%

10. 9 31 CBr 4, 0C 100% 14 1) 14, microwave, 140C, 30 min 2) 90% 33

11. 10 33 1) CrO3, 3,5-dimethylpyrazole 2) 3) Clay Scavenger 70% 1

12. Conclusions Total synthesis of (+) plicamine in 40% total yield with 10 steps Showcases the advantages of solid supported reagents Entire total synthesis without a single traditional purification eg. Column chromatography. 11