Organic Chemistry of Drug Synthesis. Volume 7

of the more important pitfalls in cancer chemotherapy. Considerable effort
has been devoted to finding drugs, so-called chemosensitizing agents, that
reverse the process. The synthesis ofone of these,biricodar( 38 )ispresented
inoutlineformomittingseveralprotection–deprotectionsteps.Onearmofthe
convergent scheme begins with the oxidation of trimethoxyacetophenone ( 31 )
with selenium dioxide to afford the corresponding acid ( 32 ). Compound 32 is
thencondensedwiththesilyl esterof pipecolic acidtoaffordthe amide;depro-
tection yields acid 33. Construction of the second moiety involves first
addition of the addition of an organometallic derivative of propargyl
bromide to but-3-ynal ( 34 ). The anion from removal of the acetylenic
protons with strong base is then treated with 3-bromopyridine. This affords
the product ( 36 ) from displacement of halogen by the terminal acetylenic
carbon. Catalytic hydrogenation then leads to intermediate 37. Esterification
of the acid ( 33 ) with alcohol 37 affords ( 38 ).^7

O

OCH 3

OCH 3

CH 3 O

31

SeO 2

O CO 2 H

OCH 3

OC0H 3

CH 3 O

32

NH CO 2 Si(CH 3 ) 3 O

OCH 3

OCH 3

CH 3 O

33

O

N CO 2 H

1.

2. H+

O=HC
34

BrMg HO 1. BuLi

N

Br

HO

N

N

H 2 HO N

N

35

36 37

O

OCH 3

OCH 3

CH 3 O

O

N O

N

O N

38

C. Miscellaneous

The design of the peptidomimetic antiviral agent (Chapter 1) ultimately
traces back to the fact that structures of these protease inhibitors in some
way act as surrogates for the natural substrate enzyme. The recent protease

1. COMPOUNDS WITH ONE HETEROATOM 119