08 Advanced Synthesis
AGM Barrett

The course will outline and discuss several total syntheses to illustrate strategic planning. The use of reagents for asymmetric synthesis and organometallic transformations will be highlighted.

Summary of Topics

1. The Endiandric Acid Cascade
Total synthesis of endiandric acids A, B, C and D (Nicolaou). Acetylene coupling; semi-hydrogenation; cascade electrocyclisations and cycloadditions; biomimetic synthesis.

2. Rifamycin S
Total synthesis of rifamycin S (Masamune, Kishi). Assembly of ansa chains; stereocontrolled aldol reactions; chelation and non-chelation control; Pummerer chemistry; macrocyclisation.

3. (-)-Roxaticin
Total synthesis of (-) roxaticin (Rychnovsky). Asymmetric hydrogenation; Brown allylboration; 1,3-dioxanes in stereocontrolled 1,3-diol assembly; polyene construction; macrocyclisation.

4. (-)-Histrionicotoxin
Total synthesis of (-) histrionicotoxin (Stork). Brown allylboration; epoxide spiroannulation and related reactions; ( Z)-iodomethylenylation; Weinreb-Woodward-Vorbruggen amide synthesis; palladium catalysed coupling reactions.

5. Strychnine
"The heroic ring by ring forging of the original strychnine assembly, which required 27 steps, resolution of enantiomers, and the use of three degradation products of the natural alkaloid as relays, now stands as an instructive inspiration for the design of synthetic alternatives" (Comments by M.E. Kuehne, 1993, on the classic synthesis of strychnine by R.B. Woodward). True or false? An overview of a recent total synthesis (Rawal). Pyrroline-diene Diels Alder reactions; allylation; palladium catalysed cyclisations; isostrychnine synthesis and conversion into strychnine.

6. Gilvocarcin
Total synthesis of gilvocarcin (Suzuki). Stereoselective C-glycoside synthesis; benzyne-furan cycloadditions; intramolecular palladium catalysed coupling chemistry.


1. Nicolaou, K.C.; Petasis, N.A.; Zipkin, R.E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5555. Nicolaou, K.C.; Petasis, N.A.; Uenishi, J.; Zipkin, R.E. J. Am. Chem. Soc. 1982, 104, 5557. Nicolaou, K.C.; Zipkin, R.E.; Petasis, N.A. J. Am. Chem. Soc. 1982, 104, 5558. Nicolaou, K.C.; Petasis, N.A.; Zipkin, R.E. J. Am. Chem. Soc. 1982, 104, 5560.

2. Masamune, S.; Choy, W. Aldrichimica Acta 1982, 15, 47 and references therein.

3. Rychnovsky, S.D.; Hoye, R.D. J. Am. Chem. Soc. 1994, 116, 1753.

4. Stork, G.; Zhao, K. J. Am. Chem. Soc. 1990, 112, 5875.

5. Rawal, V.H.; Iwasa, S. J. Org. Chem. 1994, 59, 2865 and references therein.

6. Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568.