strychnine total synthesis

Strychnine total synthesis in chemistry describes the total synthesis of the complex biomolecule strychnine. The first reported method by the group of Robert Burns Woodward in 1954 is considered a classic in this research field.

At the time it formed the natural conclusion to an elaborate process of molecular structure elucidation that started with the isolation of strychnine from the beans of ''Strychnos ignatii'' by Pierre Joseph Pelletier and Joseph Bienaimé Caventou in 1818. Major contributors to the entire effort were Sir Robert Robinson with over 250 publications and Hermann Leuchs with another 125 papers in a time span of 40 years. Robinson was awarded the Nobel Prize in Chemistry in 1947 for his work on alkaloids, strychnine included.

The process of chemical identification was completed with publications in 1946 by Robinson and later confirmed by Woodward in 1947. X-ray structures establishing the absolute configuration became available between 1947 and 1951 with publications from Johannes Martin Bijvoet and J. H. Robertson
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Woodward published a very brief account on the strychnine synthesis in 1954 (just 3 pages) and a lengthy one (42 pages) in 1963.

Many more methods exist and reported by the research groups of Magnus, Overman, Kuehne, Rawal, Bosch, Vollhardt, Mori, Shibasaki, Li, Fukuyama Vanderwal and MacMillan. Synthetic (+)-strychnine is also known. Racemic synthesises were published by Padwa in 2007 and in 2010 by Andrade and by Reissig.
In his 1963 publication Woodward quoted Sir Robert Robinson who said ''for its molecular size it is the most complex substance known''.

The molecule

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The C₂₁H₂₂N₂O₂ strychnine molecule contains 7 rings including an indoline system. It has a tertiary amine group, an amide, an alkene and an ether group. The naturally occurring compound is also chiral with 6 asymmetric carbon atoms including one quaternary one.
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Woodward synthesis

Ring II, V synthesis

The synthesis of ring II was accomplished with a Fischer indole synthesis using phenylhydrazine 1 and acetophenone derivative acetoveratrone 2 (catalyst polyphosphoric acid) to give the 2-veratrylindole 3. The veratryl group not only blocks the 2-position for further electrophilic substitution but will also become part of the strychnine skeleton. A Mannich reaction with formaldehyde and dimethylamine) produced gramine 4. Alkylation with iodomethane gave an intermediate quaternary ammonium salt which reacted with sodium cyanide in a nucleophilic substitution to nitrile 5 and then in a reduction with lithium aluminium hydride to tryptamine 6. Amine-carbonyl condensation with ethyl glyoxylate give the imine 7. The reaction of this imine with TsCl in pyridine to the ring-closed N-tosyl compound 8 was described by Woodward as a concerted nucleophilic enamine attack and formally a Pictet–Spengler reaction. This compound should form as a diastereomeric pair but only one compound was found although which one was not investigated. Finally the newly formed double bond was reduced by sodium borohydride to indoline 9 with the C8 hydrogen atom approaching from the least hindered side (this proton is removed later on in the sequence and is of no importance).
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Ring III, IV synthesis

Indoline 9 was acetylated to N-acetyl compound 10 (acetic anhydride, pyridine) and then the veratryl group was then ring-opened with ozone in aquaeous acetic acid to muconic ester 11 (made possible by the two electron-donating methoxide groups). This is an example of bioinspired synthesis already proposed by Woodward in 1948. Cleavage of the acetyl group and ester hydrolysis with HCl in methanol resulted in formation of pyridone