Organic Chemistry of Drug Synthesis. Volume 7

endogenous substances that includes not only ACE but a number of other
enzymes involved in regulation of the cardiovascular function. The construc-
tion of the bicyclic nucleus for one of these agents starts by forming the
amide ( 18 ) between trifluoroacetamide-protected cysteine ( 16 )withthe
dimethylacetal ( 17 ). Treatment of that disulfide intermediate ( 18 )with
tributylphosphine leads to reduction of the disulfide bond to a thiol in
effect cutting that precursor in two. That transient intermediate 19 is then
immediately exposed to acid. The sequence that follows can be rationalized
by assuming the thiol exchanges with one of the methoxyl groups on the
acetal function to form a seven-membered ring; the remaining acetal
methoxy is then replaced by the amide nitrogen to close the six-membered
ring. Note that the carbon atom that results from this transform ( 20 )has
not changed oxidation state as it consists of the sulfur equivalent of a carbi-
nolamine. Saponification of the trifluoroacetyl amide removes that protecting
group to reveal the primaryamine ( 21 ). This function isthen acylated with the
2-thioacetyl phenylacetic acid ( 22 ). Removal of the protecting groups on this
last intermediate affords the vasopeptidase inhibitoromapatrilat( 24 ).^4

CF 3 COHN S S NHCOCF 3

CO 2 H CO 2 H

OCH 3

H 3 CO

CO 2 CH 3

OCH 3

OCH 3

CH 3 O 2 C

NH 2 CF 3 COHN S S NHCOCF 3

H 3 CO

OCH 3

CH 3 O 2 C

NH O O NH

Bu 3 P

OCH 3

H 3 CO

CO2CH 3

HS NHCOCF 3

N O NH

S NHCOCF 3

CO 2 CH 3

N O

S NH 2

CO 2 CH 3

O

N

S

CO 2 CH 3

O

N

O

SCOCH 3 N

S

CO 2 H

O

N

O

H H SH

C 6 H 5 CO 2 H

SCOCH 3

16

17

18

19

(^2120)
22
23 24
B. Compounds with Three Heteroatoms
Sleep inducing drugs go back to the very earliest days of medicinal chemistry.
The earliest drugs comprise the barbiturates, which though effective had some

1. COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS 191