The Total Synthesis of Strychnine (1954)
strychinine
· Poison Isolated in 1818
· Used as a pestcide and in medicine as a stimulant for
the central nervous system
· Structure elucidation in 1946
· X-ray crystallographic confirmation in the early 1950 ?s
· Absolute configuration in 1956
· Challenge: 6 chiral centers and 7 rings
3For its molecular size it is the most complex
substance known. ′ ------ Sir Robert Robinson
N
OO
N
H
H
H
H
Retrosynthesis I
Retrosynthesis II
Retrosynthesis III
Synthesis of Intermediate 19
Synthesis of Intermediate 13a
Synthesis of Intermediate 10b
Epimerization of Intermediate 13a
Synthesis of Intermediate 9
Synthesis of Intermediate 35
Synthesis of Intermediate 6
Synthesis of Intermediate 5
Base-induced Conversion of 3 to 1
Reduction of Pyridone Ring
Done!
Dieckmann Condensation
Reaction type: Intramolecular Nucleophilic Acyl Substitution
· Intramolecular Claisen condensation of diesters
· The products are cyclic b-ketoesters
· 5- or 6-membered rings are favored
Example
Conclusion
·Simple reagents
+ è amazing structural transformation
Only 28 steps
· Oxidative cleavage of the veratryl ring in 17 is instructive
· Epimerization equilibrium help build stereo centers
3However, Woodward realized that the constitution of the
molecule was such that it defined its own configurations
and that a total synthesis should be relatively easy. An
elegant synthesis was planned and executed with highly
talented collaborators, again in a short time. ′
By Elkan Blout
