6518
J . Am. Chem. SOC.1983, 105, 6518-6520
THF-H,O (lO:l), 75 "C, 1 h) to furnish 20 as an oil ([(YIz3D +3.5") in 75% yield from 18. Reduction of this ketone (NaBH,, MeOH, 25 "C) gave a mixture of 21 and 22 (98%; 2:1 respectively), the acetates of which (AczO, pyridine, DMAP) were easily separated. The 7 s acetate 23 underwent hydrolysis (p-TsOH, THF-H20 (4:1), 56 "C, 12 h) to 24, which was saponified (NaOH, THF-H,O, 25 "C, 3 h) and acidified (5% aqueous HCI) to provide 4 (91% from 23), identical with the degradation product from b ~ r o m y c i n . ~For a rigorous comparison with naturally derived material, synthetic 4 was converted to triacetate 25 (68%, &OMe
R=OMe
2f8,
R=OH /-N
I
22, R = N
4
L
OMe
MeO&
12, R = C H z O H
OMe
G ,R = C H ( O M e ) ?
11, R = C H O
'2
12, R = C H O 12, R.COzH 12, R = C 0 2 M e
,-.,
% ',
0
0
wR 0
12, RI,Rz:O, X = S 0 2 P h LO, R,,Rz=O, X = H 2 , R,=OH, R z = X = H
lJ, ,:l
R=OMe R=CH2SO2Ph
I
IL
-'dJ-
&Jopsin A, Suc-Phc-Pro-Phc-NA (5 I5 pM) 3s 3 substrdtc. ( 1 . 9 pM) was incubated as in a Lvith 23 p M inhibitor and residual activity measured with Suc-Phe-Pro-Phe-NA (220 pM) as a substrate.
suggested that heterocycles containing masked reactive functionalities might act as mechanism-based irreversible inhibitors for H L elastase and cathepsin G. Therefore we prepared 3(1) and chloroisocoumarin (3-chlor0-1H-2-benzopyran-l-one)~ 3,3-dichl~rophthalide~ (2) and have found them to be potent inhibitors of several serine proteases. n
0
x 1
2
y
x = Y = c I X
=
C1.Y
=
H
Incubation of 1 and 2 with H L elastase, PP elastase, and chymotrypsin A, resulted in a rapid time-dependent inhibition of enzyme activity (Table I). While human leukocyte cathepsin G was inhibited by 2
