Construction of the thiomorpholine moiety starts by protection of the car-
boxylic acid in penicillamine ( 102 ) by reaction with hexyl dimethylsilane
(Dmhs). Condensation of 103 with 1,2-dichloroethane leads to formation
of the heterocyclic ring by sequential displacement of halogen by nitrogen
and sulfur to yield 104. Reaction of intermediate 104 with the benzophe-
none ( 101 ), leads to formation of the sulfonamide ( 105 ). Mild acid then
serves to reveal the free carboxylic acid ( 106 ). This function is then con-
verted to the acid chloride with oxalyl chloride. Treatment of this reactive
intermediate with hydroxylamine leads to acylation on nitrogen to afford
the proteinase inhibitor 107.^17
SH
NH 2
CO 2 HDmhs =C6H13(CH3)2Si^102SH
NH 2
CO 2 Dmhs
103Cl Cl
DBUS
NH104OH
+ NCl99NO100ClSO 3 H
NO101ClO 2 SNS O
N
CO 2 DmhsCO 2 DmhsSO 2105NS O
N
CO 2 HSO 2
106NS O
NS
O 2
O NHOH- (COCl) 2
- NH 2 OH
107
Endothelins comprise a group of vasoconstrictive peptides generated by
the endothelium of blood vessels, as well as other tissues. Studies on
inhibitors or frank antagonist suggest that such compounds will be of
value in treating various cardiovascular diseases. The synthesis of an
antagonist starts by forming a sulfonamide linkage. Thus, reaction of
o-bromobenzenesulfonyl chloride ( 108 ) with aminoisoxazole ( 109 ) gives
the sulfonamide ( 110 ). The somewhat acidic sulfonamide function is
then tied up as its methoxymethylene (MOM) derivative. Lithium–
halogen interchange of the bromine in 111 followed by reaction with
trimethyl borate gives the borate ester ( 112 ). Mild acid leads to the corre-
sponding boric acid derivative. Reaction of that compound with the substi-
tuted bromobenzene ( 114 ) in the presence of a palladium–triphenyl
phosphine complex leads to aryl coupling and formation of the biphenyl
( 115 ). The MOM group is lost along the line, most likely during hydrolysis
of the borate ester. Reductive amination of the aldehyde function in
- COMPOUNDS RELATED TO ARYLSULFONIC ACIDS 55