Strychnine total synthesis
[6] 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.
[16] Many more methods exist and reported by the research groups of Magnus,[17] Overman,[18] Kuehne,[19][20] Rawal,[21] Bosch,[22][23] Vollhardt,[24][25] Mori,[26][27] Shibasaki,[28] Li,[29] Fukuyama [30] Vanderwal [31] and MacMillan.
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.
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).
In order to remove the C15 alcohol group, Enol 15 was converted to tosylate 16 (TsCl, pyridine) and then to mercaptoester 17 (sodium benzylmercaptide) which was then reduced to unsaturated ester 18 by Raney nickel and hydrogen.
In the final step to (−)-strychnine 28 treatment of 27 with ethanolic potassium hydroxide caused rearrangement of the C12-13 double bond and ring closure in a conjugate addition by the hydroxyl anion.
This starting material was converted in several steps to trialkylstannane 2 which was then coupled with an aryl iodide 1 in a Stille reaction in presence of carbon monoxide (tris(dibenzylideneacetone)dipalladium(0), triphenylarsine).
The key step was an aza-Cope-Mannich reaction initiated by an amine-carbonyl condensation using formaldehyde and forming 6 in a quantitative yield: In the final sequence strychnine was obtained through the Wieland-Gumlich aldehyde (10): Intermediate 6 was acylated using methyl cyanoformate and two protective groups (tert-butyl and ) were removed using HCl / MeOH in 7.
Starting compounds tryptamine 1 and 4,4-dimethoxy acrolein 2 were reacted together with boron trifluoride to acetal 3 as a single diastereomer in an amine-carbonyl condensation / sigmatropic rearrangement sequence.
A Johnson–Corey–Chaykovsky reaction (trimethylsulfonium iodide / n-butyllithium) converted the aldehyde into an epoxide which reacted in situ with the tertiary amine to ammonium salt 5 (contaminated with other cyclization products).
A DBU mediated elimination reaction formed olefinic alcohol 10 and subsequent Swern oxidation have an unstable amino ketone 11.
In the final steps a Horner–Wadsworth–Emmons reaction (methyl 2-(diethy1phosphono)acetate) give acrylate ester 12 as a mixture of cis and trans isomers which could be coached into the right (trans) direction by application of light in a photochemical rearrangement, the ester group was reduced (DIBAL / boron trifluoride) to isostrychnine 13 and racemic strychnine 14 was formed by base-catalyzed ring closure as in the Woodward synthesis.
In the Rawal synthesis (1994, racemic) amine 1 and enone 2 were combined in an amine-carbonyl condensation followed by methyl chloroformate quench to triene 3 which was then reacted in a Diels–Alder reaction (benzene 185 °C) to hexene 4.
The three ester groups were hydrolyzed using iodotrimethylsilane forming pentacyclic lactam 5 after a methanol quench in a combination of 7 reaction steps (one of them a Dieckmann condensation).
The phenylethyl substituent was removed using ClCO2CHClCH3 and the enone group was introduced in a Grieco elimination using TMSI, HMDS then PhSeCl then ozone and then diisopropylamine forming carbamate 3.
In the final step to the Wieland-Gumlich aldehyde 7 reaction with NaH in MeOH afforded the correct epimer was followed by DIBAH reduction of the methyl ester.
The key reaction in the Vollhardt synthesis (2000, racemic) was an alkyne trimerisation of tryptamine derivative 1 with acetylene and organocobalt compound CpCo(C2H4)2 (THF, 0 °C) to tricycle 2 after deprotection of the amine group (KOH, MeOH/H2O reflux).
Subsequent reaction with iron nitrate brought about a [1,8]-conjugate addition to tetracycle 3, amine alkylation with (Z)-1-bromo-4-[(tert-butyldimethylsilyl)oxy]-2-iodobut-2-ene (see Rawal synthesis) and lithium carbonate, and isomerization of the diene system (NaOiPr, iPrOH) formed enone 4.
After ester reduction (DIBAL) to the alcohol and its TIPS protection (TIPSOTf, triethylamine), the acetal group was removed (catalytic CSA) in ketone 8.
The conversion to alcohol 10 was accomplished via a Mukaiyama aldol addition using formaldehyde, iodonation to 11 (iodine, DMAP) was followed by a Stille coupling (Pd2dba3, Ph3As, CuI) incorporating nitrobenzene unit 12.
The key step was an inverse electron demand Diels–Alder reaction of cyclophane 1 by heating in N,N-diethylaniline (dinitrogen is expulsed) followed by reduction of double bond in 2 to 3 by sodium borohydride / triflic acid and removal of the carbamate protecting group (PDC / celite) to 4.
