Strychnine total synthesis

The total synthesis of strychnine in organic chemistry describes the total synthesis of the complex biomolecule strychnine. The synthesis of strychnine has been completed a number of times over the years, beginning with the first reported synthesis by the group of Robert Burns Woodward in 1954. Woodward's synthesis is considered a classic in this research field. At the time of Woodward's report, the total synthesis symbolized the conclusion of an elaborate process of molecular structure elucidation that began with the isolation of strychnine from the beans of Strychnos ignatii by Pierre Joseph Pelletier and Joseph Bienaimé Caventou in 1818. Major contributors to this effort of structure elucidation were Sir Robert Robinson, with over 250 publications on the topic, and Hermann Leuchs (with another 125) over a span of 40 years. For his efforts, Robinson was awarded the Nobel Prize in Chemistry in 1947 for his work on alkaloids, strychnine included.

The lengthy process of the chemical identification of strychnine was completed in 1946 by Robinson, which was 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 In the years since Woodward's 1954 work, other syntheses of strychnine have been 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 syntheses were published by Padwa in 2007 and in 2010 by Andrade and by Reissig. Referring to the alkaloid in his 1963 publication, Woodward quoted Sir Robert Robinson as saying: "...for its molecular size it is the most complex substance known."

The molecule For simplicity, the ring and structure numbering below will be used throughout the descriptions of the various syntheses.

The strychnine molecule (molecular formula C21H22N2O2) is a complex structure, consisting of seven ring systems (numbered I–VII) as well as six stereocenters, all contained within 24 atoms. The molecule also possess a variety of functional groups, an indoline system in addition to a tertiary amine, amide, alkene, and an ether moiety.

Woodward synthesis (1954)

Ring II, V synthesis The synthesis of ring II was accomplished by a Fischer indole synthesis using phenylhydrazine 1 and acetophenone derivative acetoveratrone 2 (using a polyphosphoric acid catalyst) 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. Mannich reaction of 3 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. Although compound 8 should form as a diastereomeric pair, only one compound was found; which diastereomer was formed 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.

Ring III, IV synthesis Indoline 9 was acetylated to N-acetyl compound 10 using acetic anhydride and pyridine. From here, the veratryl ring was then opened using ozone in aqueous acetic acid to muconic ester 11 (this ring-opening made possible by the two electron-donating methoxide groups). This sequence is considered an example of bioinspired synthesis, proposed by Woodward in 1948. Cleavage of the acetyl group, and ester hydrolysis with HCl in methanol resulted in formation of pyridone ester 12 with additional isomerization of the exocyclic double bond to an endocyclic double bond (losing one asymmetric center in the process). Subsequent treatment with hydrogen iodide and red phosphorus removed the tosyl group and hydrolysed both remaining ester groups to form dicarboxylic acid 13. Acetylation and esterification produced acetyl diester 14, which was then subjected to a Dieckman condensation with sodium methoxide in methanol to enol 15.

Ring VII synthesis To remove the C15 alcohol group, enol 15 was converted to tosylate 16 (using TsCl and pyridine) and then to mercaptoester 17 via reaction with sodium benzylmercaptide. Mercaptoester 17 was then reduced to unsaturated ester 18 by reaction of Raney nickel and hydrogen. Further reduction with hydrogen and palladium on carbon afforded saturated ester 19. Alkaline ester hydrolysis of 19 to carboxylic acid 20 was accompanied by epimerization at C14.

Compound 20 was known from earlier strychnine degradation studies. Up to this point in the synthesis, all intermediates were obtained as racemic mixtures, but chirality was introduced at this particular step via chiral resolution using quinidine. The C20 carbon atom was then introduced by acetic anhydride to form enol acetate 21, and the free aminoketone 22 was obtained by hydrolysis with hydrochloric acid. Ring VII in intermediate 23 was closed by oxidation with selenium dioxide, a process accompanied by epimerization again at C14.

Regarding the formation of 21, this step can be envisioned as a sequence of acylation, deprotonation, and rearrangement with loss of carbon dioxide, followed by a second acylation:

Ring VI synthesis To diketone 23, sodium acetylide was added (adding the C22 and C23 carbon atoms) to give alkyne 24. This compound was reduced to the allyl alcohol 25 using Lindlar catalyst, and lithium aluminium hydride removed the remaining amide group to furnish 26. An allylic rearrangement to alcohol 27 (isostrychnine) was achieved by reaction with hydrogen bromide in acetic acid, followed by hydrolysis with sulfuric acid. In the final step, treatment of 27 with ethanol potassium hydroxide resulted in rearrangement of the C12–C13 double bond and subsequent ring closure in a conjugate addition by the hydroxyl anion, resulting in the desired (–)-strychnine product 28.

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