CO 2 C 2 H 5NH 2AcHNO34CO 2 CH 2 CF 3+35NBOC (^6) HH (^5) C 6 H 5
H
- (^36) CO 2 CH 2 CF 3
37
NH 3
CO 2 NH 2
38
I 2
HN
I
39 O
t-BOCN
I
O
40
DBU
t-BOCN
O
41
NBS
AIBn
t-BOCN
O
Br
42
CsO 2
t-BOCHN
43
CO 2 C 2 H 5 EtOH
CH 3 CN
NBASnBr
4
CO 2 C 2 H 5
t-BOCHN
43
CO 2 C 2 H 5
t-BOCHN
44
Br
AcHN CO 2 C 2 H 5
t-BOCHN
45
NHAc
(t-BuOCO) 2 O
Neuraminidase blocking activity is interestingly retained when the
central ring is contracted by one carbon atom. Note that the cyclopentane
ring in the antiviral agent peramivir ( 53 ) carries much the same
substituents as its cyclohexane-based counterpart. The presence of the
guanidine substituent, however, traces back to the tertrahydropyran
zanamivir ( 24 ). The relatively concise synthesis of peramivir starts by
methanolysis of the commercially available bicyclic lactam 46.
Reaction of the thus-obtained amino-ester witht-BOC anhydride leads
to theN-protected intermediate ( 47 ). The key reaction involves addition
of both a functionalized carbon substituent and a hydroxyl group in a
single step. Reaction of the nitroalkane ( 48 ) with phenyl isocyanate
leads to the formation of a nitrone. That very reactive species then
undergoes 2þ3 cycloaddition to the double bond in the cyclopentene
( 47 ). The isoxazolidine ( 49 ) is the predominant isomer from that
reaction. Catalytic hydrogenation then cleaves the scissile nitrogen-
to-oxygen bond leading to ring opening and formation of the corre-
sponding aminoalcohol. This compound is converted to acetamide ( 50 )
with acetic anhydride. The ring amino group is next revealed by
removal of thet-BOC group by means of acid to yield 51. An exchange
reaction of that primary amine with pyrazole carboxamidine ( 52 ) then
introduces the guanidine group. Thus the antiviral compound 53
is obtained.^10
28 ALICYCLIC COMPOUNDS