Stork Quinine Total Synthesis
The Stork quinine synthesis starts from chiral (S)-4-vinylbutyrolactone 1. The compound is obtained by chiral resolution and in fact, in the subsequent steps all stereogenic centers are put in place by chiral induction: the sequence does not contain asymmetric steps.
| Stork quinine synthesis | Introducing C8 and nitrogen |
The lactone is ring-opened with diethylamine to amide 2 and its hydroxyl group is protected as a tert-butyldimethyl (TBS) silyl ether in 3. The C5 and C6 atoms are added as tert-butyldiphenylsilyl (TBDPS) protected iodoethanol in a nucleophilic substitution of acidic C4 with LDA at -78°C to 4 with correct stereochemistry. Removal of the silyl protecting group with p-toluenesulfonic acid to alcohol 4b and ring-closure by azeotropic distillation returns the compound to lactone 5 (direct alkylation of 1 met with undisclosed problems).
The lactone is then reduced to the lactol 5b with diisobutylaluminum hydride and its liberated aldehyde reacts in a Wittig reaction with methoxymethylenetriphenylphosphine (delivering the C8 atom) to form enol ether 6. The hydroxyl group is replaced in a Mitsunobu reaction by an azide group with diphenylphosphoryl azide in 7 and acid hydrolysis yields the azido aldehyde 8.
| First ring closure | Second ring closure |
The methyl group in 6-methoxy-4-methylquinoline 9 is sufficiently acidic for nucleophilic addition of its anion (by reaction with LDA) to the aldehyde group in 8 to form 10 as a mixture of epimers. This is of no consequence for stereocontrol because in the next step the alcohol is oxidized in a Swern oxidation to ketone 11. A Staudinger reaction with triphenylphosphine closes the ring between the ketone and the azide to the tetrahydropyridine 12. The imine group in this compound is reduced to the amine 13 with sodium borohydride with the correct stereospecificity. The silyl protecting group is removed with hydrogen fluoride to alcohol 14 and then activated as an mesyl leaving group by reaction with mesyl chloride in pyridine which enables the third ring closure to 15. In the final step the C9 hydroxyl group was introduced by oxidation with sodium hydride, dmso and oxygen with quinine to epiquinine ratio of 14:1.
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