Shikimic acid is not only an important intermediate in biosynthesis, but also a useful chiral reagen — Analytical Chemistry Chemistry Question
Synthesis of Tamiflu
Shikimic acid is not only an important intermediate in biosynthesis, but also a useful chiral reagent leading to the production of various valuable medicines because the molecule of shikimic acid contains several chiral carbons.
Tamiflu is now a specific medicine for the inhibition of influenza virus propagation, and can be synthesized starting from shikimic acid which was derived from natural Star anise (Illicium verum). A part of the synthetic scheme is shown below:
[VISUAL]
Show chemical reagents necessary for the transformations of a, b, c, d, e, and f in the above scheme.
Model Answer
a: EtOH / SOCl2
b: 3-pentanone / H+
c: MeSO2Cl / Et3N
d: NaHCO3
e: NaN3 / NH4Cl
f: NaN3 / NH4Cl
Show the reaction mechanism for the transformation of b.
Model Answer
The mechanism involves acid-catalyzed ketalization (acetonide formation) of the 3,4-diol of shikimic acid ethyl ester with 3-pentanone. It proceeds via protonation of the carbonyl oxygen of 3-pentanone, nucleophilic attack by one of the hydroxyl groups of the diol, proton transfer, elimination of water to yield an oxocarbenium intermediate, and subsequent intramolecular ring closure by nucleophilic attack of the second hydroxyl group, followed by deprotonation to yield the cyclic diethyl ketal protecting group.
Show the molecular structure of intermediate A.
Model Answer
Intermediate A is ethyl (3R,4S,5S-4,5-epoxy-3-(3-pentyloxy)cyclohex-1-ene-1-carboxylate. It is formed by the selective reduction of the 3-pentanone ketal (acetonide) using Et3SiH and TiCl4 (leaving a 3-pentyl ether at C3 and a free OH group at C4), followed by base-mediated (NaHCO3) intramolecular SN2 displacement of the C5-mesylate by the C4-alkoxide to form the epoxide ring.
How many stereoisomers are possible in the molecular structure of Tamiflu?
Model Answer
8 isomers