lithiated on the pyrrole ring. Condensation of that species with the highly
protected aminosugar ( 34 ) results in addition of the anion to the imine
function on the sugar. Deprotection of that product ( 35 ) in several steps
then affords 36.^6
N
NNC 6 H 5 CH 2 OCH 2 OCH 3
BuLi N
NNC 6 H 5 CH 2 OCH 2 OCH 3LiNOOTbdmsO
Tbdms = tBu(CH 3 ) 2 Si–N
NNC 6 H 5 CH 2 OCH 2 OCH 3HNOOTbdmsO
Bu 4 N+F+
H 3 O+N
NHNOHHNHO OHHOH 2(^3233)
34
35
36
The pteridine, folic acid, comprises one of the essential factors required
for synthesis of DNA and by extension cell proliferation. As a result, folate
antagonists have been intensively investigated as potential antitumor
compounds. The pteridine-based antagonist methotrexate, which was devel-
oped many years ago, simply comprises folic acid in which the side-chain
amine is methylated and nitrogen replaces the oxygen atom at the 4 pos-
ition. This drug is widely used as an antitumor compound. Methotraxate
in fact comprises the “M” in the acronym of the many multidrug cocktails
used by oncologists. Most of the more recent folate antagonist, as exempli-
fied by palitrexate ( 202 ) and pelitrexol ( 213 ) described later in this chapter,
retain the two fused six-membered rings found in folic acid and replace the
side-chain amine group by a methylene group. Contraction of one of the
rings, is interestingly consistent with folate antagonism. The first few
steps in the construction of the nucleus of pemetrexed ( 46 ) follow a
well-precedented scheme. Reaction of the enolate from ethyl cyanoacetate
( 37 ) with the methyl acetal from bromoacetaldehyde ( 38 ) leads to the alky-
lation product ( 39 ). Condensation of 39 with guanidine then forms the pyr-
imidine ( 40 ). The transient side-chain aldehyde from treatment of the
compounds with acid then forms an imine with the adjacent amino group,
thus closing the fused five-membered ring ( 41 ). The remaining primary
- COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS 193