Woodward / Doering Formal Quinine Total Synthesis
The 1944 Woodward / Doering synthesis starts from 7-hydroxyisoquinoline 3 for the quinuclidine skeleton which is somewhat counter intuitive because one goes from a stable heterocyclic aromat to a completely saturated bicyclic ring. This compound (already known since 1895) is prepared in two steps.
| Woodward/Doering quinine synthesis part I | Part II |
The first reaction step is condensation reaction of 3-hydroxybenzaldehyde 1 with (formally) the diacetal of aminoacetaldehyde to the imine 2 and the second reaction step is cyclization in concentrated sulfuric acid. Isoquinoline 3 is then alkylated in another condensation by formaldehyde and piperidine and the product is isolated as the sodium salt of 4.
| Woodward/Doering quinine synthesis part III |
Hydrogenation at 220°C for 10 hours in methanol with sodium methoxide liberates the piperidine group and leaving the methyl group in 5 with already all carbon and nitrogen atoms accounted for. A second hydrogenation takes place with Adams catalyst in acetic acid to tetrahydroisoquinoline 6. Further hydrogenation does not take place until the amino group is acylated with acetic anhydride in methanol but by then 7 is again hydrogenated with Raney nickel in ethanol at 150°C under high pressure to decahydroisoquinoline 8. The mixture of cis and trans isomers is then oxidized by chromic acid in acetic acid to the ketone 9. Only the cis isomer crystallizes and used in the next reaction step, a ring opening with the alkyl nitrite ethyl nitrite with sodium ethoxide in ethanol to 10 with a newly formed carboxylic ester group and an oxime group. The oxime group is hydrogenated to the amine 11 with platinum in acetic acid and alkylation with iodomethane gives the quaternary ammonium salt 12 and subsequently the betaine 13 after reaction with silver oxide.
Quinine's vinyl group is then constructed by Hofmann elimination with sodium hydroxide in water at 140°C. This process is accompanied by hydrolysis of both the ester and the amide group but it is not the free amine that is isolated but the urea 14 by reaction with potassium cyanate. In the next step the carboxylic acid group is esterified with ethanol and the urea group replaced with a benzoyl group. The final step is a claisen condensation of 15 with ethyl quininate 16, which after acidic workup yields racemic quinotoxine 17. The desired enantiomer is obtained by chiral resolution with the chiral dibenzoyl ester of Tartaric acid. The conversion of this compound to quinine is based on the Rabe/Kindler chemistry discussed in the timelime.
Read more about this topic: Quinine Total Synthesis
Famous quotes containing the words woodward, formal, total and/or synthesis:
“What you don’t understand about this town is that they can fight about issues all they want, but they don’t really care about them. What they really care about is who they sit next to at dinner.”
—Anonymous “Prominent Woman,” Washington, DC, socialite. As quoted in The Agenda, ch. 20, by Hillary Rodham Clinton, to Bob Woodward (1994)
“True variety is in that plenitude of real and unexpected elements, in the branch charged with blue flowers thrusting itself, against all expectations, from the springtime hedge which seems already too full, while the purely formal imitation of variety ... is but void and uniformity, that is, that which is most opposed to variety....”
—Marcel Proust (1871–1922)
“The word infant derives from Latin words meaning “not yet speaking.” It emphasizes what the child cannot do and reflects the baby’s total dependence on adults. The word toddler, however, demonstrates our change in perspective, for it focuses on the child’s increased mobility and burgeoning independence.”
—Lawrence Kutner (20th century)
“It is in this impossibility of attaining to a synthesis of the inner life and the outward that the inferiority of the biographer to the novelist lies. The biographer quite clearly sees Peel, say, seated on his bench while his opponents overwhelm him with perhaps undeserved censure. He sees him motionless, miserable, his head bent on his breast. He asks himself: “What is he thinking?” and he knows nothing.”
—Andre Maurois (1885–1967)