Total Synthesis Highlights

77. Catalytic Asymmetric Synthesis of Quinine and Quinidine
The tetracyclic alkaloid quinine 1 and the diastereomeric alkaloid quinidine 2 share a storied
history. Eric Jacobsen of Harvard recently completed (J. Am. Chem. Soc. 2004, 126, 706.)
syntheses of enantiomerically-pure 1 and of 2. For each synthesis, the key reaction for establishing
the asymmetry of the target molecule was the enantioselective conjugate addition developed by
the Jacobsen group.
For both 1 and 2, the synthesis started with the alkenyl amide 3. Salen-mediated conjugate
addition proceeded with remarkable induction, to give 5 in 92% ee as a mixture of diastereomers.
Reduction and cyclization followed by deprotonation and kinetic quench delivered the
enantiomerically-enriched cis dialkyl piperidine 6. Homologation of the two sidechains then gave
the alkenyl boronic ester 8.
The quinoline portion of the target alkaloids was prepared by condensing p-anisidine 9 with ethyl
propiolate, followed by bromination. Coupling of 10 with the boronic ester 8 proceeded to give 11,
the intermediate for the synthesis of both 1 and 2. Selective direct epoxidation of 11 using the
usual reagents failed, but Sharpless asymmetric dihydroxylation was successful, providing the diol
in > 96:4 diastereoselectivity, with only traces of the tetraol and of the product from
dihydroxylation of the terminal vinyl group. The diol could be converted cleanly to the desired
epoxide 11. Deprotection followed by cyclization led to quinine 1. Preparation of the
diastereomeric epoxide, using AD-mix-α, followed by cyclization gave quinidine 2. The brevity of
the preparation of these two classical alkaloids is a testament to the power of reagent-controlled
synthesis.