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.Nicolaou, K. C.; Sorensen, E. J. (1996). Classics in Total Synthesis: Targets, Strategies, Methods. Wiley. .K. C. Nicolaou, Dionisios Vourloumis, Nicolas Winssinger, Phil S. Baran The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century Angewandte Chemie International Edition 2000; Volume 39, Issue 1, Pages: 44-122
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. See also: 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 BijvoetBijvoet , Schoone and Bokhoven , Kon. Ned. Akad. Wet., 50, No 8, 51, No. 8, 52, No. 2 (1947–49) 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,Total Synthesis of (−)-Strychnine via the Wieland-Gumlich Aldehyde Angewandte Chemie International Edition Volume 38, Issue 3, 1999, Pages: 395-397 Daniel Solé, Josep Bonjoch, Silvina García-Rubio, Emma Peidró, Joan Bosch Vollhardt, Mori, Shibasaki, Li, Fukuyama Vanderwal and MacMillan. Synthetic (+)-strychnine is also known.Not counted:an unpublished method by Gilbert Stork, Lecture at the Ischia School of Organic Chemistry, Ischia Porb, Italy, September 211992. 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."R. Robinson "Molecular structure of Strychnine, Brucine and Vomicine Prog. Org. Chem., 1952; 1 ,2
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.
Magnus synthesis (1992) Woodward's synthesis of strychnine stood as the only one for nearly four decades. In 1992, Magnus and co-workers reported a new pathway to strychnine via the synthesis of one of its many degradation products, the Wieland-Gumlich aldehyde. Beginning from the aldehyde 1, the "relay compound" 2 was achieved over the course of four reaction steps. This relay compound could be then be transformed into the target strychnine 3 in nine steps.
Overman synthesis (1993) The Overman synthesis of strychnine took a chiral cyclopentene compound 1 as the starting material, obtained by enzymatic hydrolysis of cis-1,4-diacetoxycyclopent-2-ene (not pictured). This starting material was converted in several steps to trialkylstannane 2, which was then coupled to aryl iodide 3 in a Stille reaction using a (tris(dibenzylideneacetone)dipalladium(0) catalyst, triphenylarsine, and carbon monoxide.
The cyclic alkene in enone 4 was converted to an epoxide using tert-butyl hydroperoxide; the adjacent carbonyl group was then converted to an alkene in a Wittig reaction using Ph3P=CH2, and the TIPS group was hydrolyzed (TBAF) and replaced by a trifluoroacetamide group (NH2COCF3, NaH) resulting in compound 5. Cyclization of 5 using sodium hydride opened the epoxide ring, and the trifluoroacetyl group was removed using potassium hydroxide, affording azabicyclooctane 6.
The key step of the synthetic pathway was an aza-Cope-Mannich reaction, initiated by an amine-carbonyl condensation using paraformaldehyde and heating in order to form intermediate 7 in nearly quantitative yield.
In the closing stages of the synthesis, intermediate 7 was reacted with methyl cyanoformate and catalytic amounts of hydrochloric acid to close the indoline system to form alcohol 8. Conversion of alcohol 8 to the Wieland-Gumlich aldehyde 9 featured a reduction of the alkene bond using zinc powder, followed by epimerization then reduction of the –CO2Me ester group.
The final step of the synthesis was a transformation of the Wieland-Gumlich aldehyde 9 to the final (–)-strychnine 10 using a method previously reported.
Kuehne synthesis (1993) The Keuhne synthesis concerns the formation of racemic (±)-strychnine. Starting compounds tryptamine 1 and 4,4-dimethoxy acrolein 2 were reacted together with boron trifluoride to form acetal 3 as a single diastereomer in an amine-carbonyl condensation / sigmatropic rearrangement sequence.
Hydrolysis with perchloric acid afforded aldehyde 4. A Johnson–Corey–Chaykovsky reaction (reagents trimethylsulfonium iodide / n-butyllithium) converted 4 to an epoxide, which reacted in situ with the tertiary amine to ammonium salt 5 (contaminated with other cyclization byproducts). Reduction (H2 with Pd/C) removed the benzyl group to give alcohol 6. Reduction of 6 using sodium cyanoborohydride, and acylation (reagents acetic anhydride / pyridine) produced 7 as a mixture of C17 epimers. The ring closure of ring III to intermediate 8 was achieved with an aldol reaction using lithium bis(trimethylsilyl)amide, using only the epimer with correct configuration. Subsequent reduction of 8 using sodium borohydride, followed by acylation resulted in epimeric diacetate 9.
A DBU-mediated elimination reaction formed olefinic alcohol 10, and subsequent Swern oxidation give the unstable amino ketone 11. In the final steps, a Horner–Wadsworth–Emmons reaction with methyl 2-(diethyl-1-phosphono)acetate provide acrylate ester 12 as a mixture of cis and trans isomers which could be converted into the desired trans isomer via application of light in a photochemical rearrangement. The ester 12 was reduced (reagents DIBAL / boron trifluoride) to isostrychnine 13, and racemic strychnine 14 was formed by base-catalyzed ring closure, as it was in the Woodward synthesis.
In 1998, Kuehne and co-workers were able to synthesize chiral (–)-strychnine; in this synthesis the original starting material was derived from chiral tryptophan.
Rawal synthesis (1994) This stereocontrolled synthesis achieved by Rawal and co-workers begins with the conversion of nitrile 1 to aniline 2, which is then coupled to the unsaturated aldehyde component 2a to form diene 3. This intermediate then underwent an intramolecular Diels–Alder reaction to form hexane 4. Hydrolysis of all the present ester groups and quenching with methanol formed lactam 5. The available amine in 5 was alkylated using a TBS-protected vinyl iodide component to give intermediate 6. Heck reaction of the vinyl iodide moiety, followed by removal of the TBS-protecting group yielded isostrychnine 7. In the last step of the pathway, 7 is converted to the desired strychnine product 8 by base-mediated isomerization.