Quinine total synthesis

The subject has also been attended with some controversy: Gilbert Stork published the first stereoselective total synthesis of quinine in 2001, meanwhile shedding doubt on the earlier claim by Robert Burns Woodward and William Doering in 1944, claiming that the final steps required to convert their last synthetic intermediate, quinotoxine, into quinine would not have worked had Woodward and Doering attempted to perform the experiment.

A 2001 editorial published in Chemical & Engineering News sided with Stork, but the controversy was eventually laid to rest once and for all when Robert Williams and coworkers successfully repeated Woodward's proposed conversion of quinotoxine to quinine in 2007.

The molecule is optically active with five stereogenic centers (the N1 and C4 constituting a single asymmetric unit), making synthesis potentially difficult because it is one of 16 stereoisomers.

The C5 and C6 atoms are added as tert-butyldiphenylsilyl (TBDPS) protected iodoethanol in a nucleophilic substitution of acidic C4 with lithium diisopropylamide (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 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.