Organic Chemistry of Drug Synthesis. Volume 7

(C 6 H 5 )P CO 2 CH 3

O OSiMe(CH 3 ) 2 tBu OSiMe(CH^3 )^2 tBu

N

F

N

N

SO 2 CH 3

79

+

N

F

N

N

SO 2 CH 3

81

CH 3

80

CH=O

O

CO 2 CH 3

1. HF


2. NaBH 4

N

F

N

N

SO 2 CH 3

OH OH

CO 2 CH 3

82

NaOH

N

F

N

N

SO 2 CH

OH OH

CO 2 Na

83

H 3 C

H 3 C H 3 C

Variously substituted benzyl diamino pyrimidines have a venerable
place in the history of antibiotics. These drugs, exemplified by the still
widely used, trimethoprim, are known to inhibit the enzyme dihydrofolate
reductase, crucial for bacterial replication. A very potent recently intro-
duced example has shown promise for treating infections by antibiotic
resistant bacteria. The synthesis of a fragment necessary for building a
fused ring begins with aluminium chloride catalyzed acylation of bis-
sylilated acetylene ( 84 ) with carboxycyclopropyl chloride. The reaction
interestingly stops with the introduction of a single acyl function ( 85 ).
The newly introduced ketone is then reduced to the corresponding
alcohol ( 86 ), with sodium borohydride. Mitsonobu reaction of this
alcohol with phenol 87 leads to the alkylation product, ether ( 88 ). This
product undergoes a internal 2þ4 electrocyclic addition on heating
forming a dihydropyran ring and thus product 89. The ester grouping is
then subjected to a reduction-back oxidation sequence in order to convert
ester group to the corresponding aldehyde ( 90 ). Aldol condensation of the
3-anilidopropionitrile carbonyl function, probably proceeds initially to
adduct 91. The double bond then shifts out of conjugation with the aro-
matic ring to give 92 as the observed product. The reaction of intermediate
92 with guanidine can be viewed for bookkeeping purposes as involving
addition of one of the guanidine nitrogens to the nitrile while another dis-
places the anilide by an addition–elimination step to close the pyrimidine
ring. Thus, the antibacterial agenticlaprim( 93 ) is obtained.^13

2. COMPOUNDS WITH TWO HETEROATOMS 125