by its trade name Tamiflu, has focused considerable attention on this drug.
A significant amount of work has been devoted to its preparation in the
expectation of the very large quantities that would be required in the
event that the pandemic materializes. The choice of starting material is
constrained by the fact that virtually every carbon atom on the six-
membered ring in the molecule bears a chirally defined substituent. All
the early syntheses start with either shikimic ( 25 ) or gallic acid from
plant sources. A typical approach involves construction of the epoxide
27 as an early step. Shikimic acid is first converted to its ethyl ester. The
two syn disposed adjacent hydroxyl groups are then tied up as the
acetonide ( 26 ) by reaction with acetone. The remaining free alcohol is
then converted to its mesylate by means of methanesulfonyl chloride.
Hydrolysis of the mesylate followed by reaction with base leads to internal
displacement of the mesylate and formation of the key epoxide ( 27 ).
The free hydroxyl group is then protected as its methoxymethylene ether
(MEM) ( 28 ). Reaction with the nucleophile (sodium azide) then serves
to open the oxirane to give the azide ( 29 ). The next series of steps in
essence establishes the presence of adjacent trans disposed amino
groups. The free hydroxyl is thus first converted to a mesylate; catalytic
hydrogenation then reduces the azide to a primary amine ( 30 ). This dis-
places the adjacent mesylate to form an aziridine ( 31 ). Treatment of this
intermediate or a derivative with acetic anhydride then affords the activated
intermediate ( 32 ).
O CO 2 HAcHN HNHOOHNH
24 NH^2HO CO 2 H
HO
OH
25HO CO 2 C 2 H 5O
27CO 2 C 2 H 5OMEMO CO 2 C 2 H 5 MEMO
HO
N 3- MsCl2. H
2
MEMO CO 2 C 2 H 5
MsO
NH 2MEMO CO 2 C 2 H 5AcHNCO 2 C 2 H 5OHO
O26- MsCl2. H+
3. B–
30 29 28CO 2 C 2 H 5N 3AcHNHO3132CO 2 C 2 H 5N 3CO 2 C 2 H 5NH 2AcHNO
NHAc33 3426 ALICYCLIC COMPOUNDS