The Discovery of GS-9131, an Amidate Prodrug of a Novel Nucleoside Phosphonate HIV Reverse Transcriptase Inhibitor - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 226

the diphosphate metabolite of 22 bound in the active site of HIV RT was solved
and confirmed the binding orientation from the original modeling studies. 30
Overall, the unique and promising resistance profile of 22, coupled with the
potency and selectivity of the inhibitor toward RT, met our stringent target
profile criteria and the program moved into the prodrug development phase.

10.2.5 Synthesis
In order to pursue a prodrug strategy on the target compound, an ecient
route to multigram quantities was required. Compound 22 is a complex
molecule, containing two chiral centers, a unique acetal-aminal configuration,
and a fluorine, so the development of a viable stereocontrolled synthesis war-
rants some mention. 25 The most successful route, shown in Figure 10.6, utilized
the readily available fluoro sugar 23, which avoided the need to perform
fluorine chemistry.
Stereochemical control of the nucleobase stereocenter was performed via S N 2
displacement of the anomeric a-bromide readily formed from 23. The next key
intermediate was glycal 26, which was prepared through decarboxylative
dehydration of acid 25. Without the 2 0 -b-F present, the glycal intermediate was
suciently stable to withstand high-temperature methods for effecting de-
carboxylation. 17 However, in the presence of 2 0 -b-F the glycal was prone to
aromatization and so an alternative lower temperate method using Mitsunobu
conditions had to be developed. The glycal 26 was formed in situ and pre-
ferentially activated on the opposite face to the purine ring by sterically large
activating groups such as iodine or phenylselanyl. 17 This facial activation, in
turn, directed nucleophilic attack of the phosphonate alcohol onto the same
face as the purine ring to generate 27 with regio- and stereoselective control.

OMe

OMe

N

N

N

N

HO O

BzO

HO

N

N

N

OBz

N

O

O

F

O

F

F

OH
25

OBz

OH

24

23

OMe

OMe

NH 2

N

N

N

N N

N OEt

OH

EtO

N

HO

N

P O N

N

P O N

N O

O

O

O F

F

O

I

F

22 I 26

27

Figure 10.6 General synthesis scheme for 22.