Sodium azide again opens a strained reactive three-membered ring. There
is thus obtained the acetamido azide ( 33 ). Repeat of the sequence, mesylate
formation followed by catalytic hydrogenation leads to formation of a
new aziridine ( 33 ), in which the ring has moved over by one carbon
atom. Reaction of this last intermediate with 3-pentanol in the presence
of base leads to opening the aziridine ring to give the corresponding
ether. The azide in this last intermediate is again reduced with hydrogen.
Finally ( 34 ) is obtained.6–8
The importance of this drug to meet a potential worldwide pandemic
has attracted the attention of academic chemists. This finding has
resulted in the development of a relatively short but elegant synthesis.
The approach is notable in that it does not involve difficult to obtain
natural product starting material and completely obviates the use of
potentially explosive azide intermediates. The first step involves building
the carbocyclic ring equipped with a chiral carbon atom that will
determine the stereochemistry of the many remaining ring substituents.
Thus, 2þ4 cycloaddition of acrylate 5 to cyclobutadiene in the pre-
sence of the pyrrolidine derivative ( 36 ) as a chiral catalyst affords the
ester ( 37 ) as a virtually pure optical isomer. The ester group is then con-
verted to an amide ( 38 ) by simple interchange with ammonia. Reaction
with iodine under special conditions leads to the nitrogen counterpart of
an internal iodo-lactonization reaction and formation of the bridged
iodolactam ( 39 ). The amide nitrogen is then protected as its tert-
butoxycarbonyl derivative. Dehydroiodination with DBU introduces a
double bond giving 41. Free radical bromination of that intermediate
with N-bromosuccinimide (NBS) proceed with the shift of the olefin
to give the allylic bromide 42. Dehydrobromination with cesium oxide
introduces an additional double bond in the ring. The presence of
ethanol leads the lactam ring to open at the same time. (For ease in visu-
alization, the product diene ( 43 ) is drawn both as produced and in the
orientation that matches that in the scheme above.) The second nitrogen
required for the product is introduced by an unusual novel reaction. The
product ( 44 ) obtained from treatment of diene 43 with acetonitrile and
NBS in the presence of stannic bromide can be rationalized by positing
initial addition of bromide to the olefin to form a cyclic bromonium ion;
addition of the unshared pair of electrons on the nitrile nitrogen would
account for the connectivity. Hydrolysis of the initial imine-like inter-
mediate would account for the observed product 44. Treatment with
base leads to internal displacement and formation of the aziridine ring
in 45. Reaction as above with 3-pentanol followed by removal of the
t-BOC group affords oseltamivir (34).^9
- MONOCYCLIC COMPOUNDS 27