Physostigmine - Synthesis

Synthesis

Physostigmine has two chiral carbon atoms. Therefore, attention needs to be paid to the synthesis of the correct diastereomers. There are 71 syntheses of physostigmine; 33 yield racemic mixtures, 38 yield a pure chiral product. The first total synthesis of physostigmine was achieved by Julian and Piki in 1935. It is summarized in Figure 3. The main goal of Julian’s physostigmine synthesis was to get the intermediate key compound, l-eseroline 10. Then, 10 would be easily converted to physostigmine. In one of his earlier works Julian synthesized the ring of physostigmine from starting material, 1-methyl-3-formyl oxindole, which was discovered by Friedlander. However, he faced the problems that the starting material was expensive, and the reduction of a nitrile to an amine (similar to the reaction of 6 to 7) with sodium and alcohol did not result in good yield. In his second work “Studies in the Indole Series III,” he had improved the yield of amine from nitrile significantly by using palladium and hydrogen.

The Julian physostigmine synthesis was started from phenacetin 1 because 1 was inexpensive. First, 1 was added to sodium powder and dimethyl sulfate under xylene while being heated to produce 2. Then, 2 was converted to anilide 3 by reacting with a-bromopropionyl bromide. When 3 was treated with an excess of aluminium chloride, the ethoxyl group of 3 was cleaved, and then heating and working up of the mass was done to give a high yield of 4. Next, 4 was ethylated by ethyl sulfate to produce 5. 5 was then treated with chloroacetoniltrile and sodium ethoxide or sodium to yield 6. The nitrile of 6 was reduced to the amine to give 7 by Palladium and hydrogen. The amine of 7 was methylated, then reacting with methyl iodide followed by hydrolysis to produce 8. By successive action of d-camphorsulfonic acid and d-tartaric acid, this amine was resolved into its enantiomers in excellent yield. As a result, l-amine of 8 was reduced by sodium and alcohol and yielded more than 80% of l-eserethole 9.

Because the yields of all the above steps were very good and those reactions required little time, l-eserethole was easy to achieve. 9 was then converted to l-eseroline 10 smoothly by dissolving it in petroleum ether and anhydrous aluminum chloride while gently boiling the mixture. The conversion of l-eseroline into physostigmine was easy to achieve by treating with methyl isocynate, which was described by Polonovski and Nitzberg. As a result, Julian had completely synthesized d,l-eserethole for the first time. Consequently, the first synthesis of physostigmine was completed.

However, there are drawbacks in Julian’s synthesis. First, the chemical resolution of 8 is unreliable, and the chemical resolution of d,l-eserethole 9 gives optically pure enantiomers after eight recrystallizations of its tartrate salt. Second, the reaction from 8 to 9 requires a large amount of Na. As a result, Julian’s synthesis needed to be improved.

Most recently, Mukund and his group have described a powerful method to construct the quaternary carbon center by using the Wittig olefination-Claisen rearrangement. The synthesis starts with the Wittig olefination of o-nitroacetophenone 11. 11 is reacted with allyloxymethylenetriphenylphosphorane to produce an allyl vinyl ether 12. 12 is an inseparable mixture of E- and Z- isomers, but the NMR signals of the E- and Z-isomers are well separated in the olefinic region. Therefore, the ratio (5:1) of these isomers is identified. The allyl vinyl ether 12 is then refluxed in xylene. This reaction goes through the Claisen rearrangement to yield 85% of 13. The aldehyde group of 13 is protected by adding p-TSA, ethylene glycol, and toluene while refluxing. Then, ozone gas and dimethyl sulfide are added into the solution in DCM at 00C and give the new aldehyde 14. This aldehyde is reduced to alcohol 15 by reacting with sodium borohydride in aqueous THF. The alcohol of 15 is converted to amine 16 by adding DIAD and triphenyl phosphine, followed by phthalimide. The reaction is later reacted with methylamine while refluxing. The nitro of 16 is then reacted with methanol, Raney nickel, and hydrogen to give diamine 17 in 82% yield. Acetal of 17 is hydrolyzed with p-TSA in refluxing aqueous THF to produce tricyclic compound 18 in 65% yields. 19 is easy to achieve by adding ethyl acetate, aqueous formalin and followed 10% catalytic, Pd-C, under hydrogen. Then, 19 is converted to esermethole 20, an intermediate in the synthesis of physostigmine. Esermethole 20 is achieved in 70% yield by adding N-bromosuccinimide (NBS) to DMF at 00C, and then sodium methoxide is added in the presence of cuprous iodide with heat. Finally, esermethole 20 is demethylated with boron tribromide; then the mixture is treated with phenol, NaH, THF, and methylisocyanate resulting in the crystalline product, Physostigmine. As a result, a new and efficient synthesis of physostigmine was successfully developed.