Sanochemia Industrial Production
The method outlined by Jordis in 1999 forms the basis for industrial galanthamine production.
| Narwedine synthesis part A | Narwedine synthesis part B |
This method is based on electrophilic halogenation of 3,4-dimethoxybenzaldehyde 1 (accessible from isovanillin) with bromine / acetic acid to organobromide 2 followed by regioselective demethoxylation with sulfuric acid to phenol 3. This compound reacts in a reductive amination (sodium borohydride) with tyramine 4 to amine 5 which is formylated with ethyl formate and formic acid in dioxane in the next step to compound 6. An oxidative phenol coupling takes place next with Potassium ferricyanide and potassium carbonate in toluene to 7. The C8a-C14 bond is formed in the first step followed by a Michael addition of the other phenolic group to the newly formed enone group. The reaction step creates two stereocenters leading to two diastereomeric pairs of enantiomers. By the nature of the ABD skeleton the desired S,S/R,R pair is the major product formed and the other pair S,R/R,S is removed in workup. The ketone group is protected as the ketal 8 with 1,2-propylene glycol enabling the organic reduction by lithiumaluminiumhydride of both the bromine group and the formyl group. In the second phase the ketal group is removed (hydrochloric acid) forming racemic (S,S/R,R) narwedine 9.
Enantiopure (-)-narwedine is obtained via the dynamic chiral resolution method pioneered by Shieh/Carlson and in the final step the ketone is reduced to the alcohol with L-selectride.
| reduction of (-)-narwedine to (-)-galanthamine as the bromide |
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This final step is enantioselective producing the desired S,S,R compound because approach of H- is restricted to the Si face as the Re face is shielded by the DB ring system. Formation of the S,S,S epimer is also avoided by keeping reaction temperature below -15°C.
Read more about this topic: Galanthamine Total Synthesis
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