â-Amino-thiols Inhibit Zn-Metallopeptidase
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3457
(2H, m, CH2CH2CONH2), 2.15 (2H, t, CH2CONH2), 2.57 (2H,
ABX J ) 16, 6 Hz, CH2COOH), 3.35 (1H, m, BocNHCH), 6.86
(1H, s, CONH2), 7.33 (1H, s, CONH2), 7.86 (3H, br s, NH3+);
SM (ES) (M + H)+ m/z ) 161.3. Anal. (C6H12N2O3).
4,4′-(Disu lfa n ed iyl)bis[m eth yl (2SR)-2-(Cbz-a m in o)bu -
ta n oa te] or DL-(Z)-Hom ocystin e-OMe (20). This compound
was synthesized as previously described32 (96% yield): Rf )
0.46 in AcEt/CH2Cl2 (1/9); 1H NMR (DMSO-d6) δ 1.83-2.09
(2H, m, CH2CH2S), 2.68 (2H, t, CH2S), 3.58 (3H, s, COOCH3),
4.13 (1H, m, CHCOOMe), 4.98 (2H, s, CH2 Ph), 7.28 (5H, m,
Ph), 7.75 (1H, d, Bzl OCONH). Anal. (C26H32N2O8S2) C, H,
N.
3-[(2SR)-2-(Boc-a m in o)-1-h yd r oxyet h yl]ben zoic Acid
(26). The R-amino ester 25 (1 equiv) was reduced in dry EtOH/
THF (8 mL/mmol) at 0 °C by NaBH4 (4 equiv) and LiCl (4
equiv) as previously described.49 This compound (1 equiv) was
dissolved in MeOH (2 mL/mmol), and 1 N NaOH (3 equiv) was
added at 0 °C. After classical treatment, 3-[(2SR)-2-(Boc-
amino)-1-hydroxyethyl]benzoic acid (26) (83% yield) was ob-
1
tained: Rf ) 0.58 in CH2Cl2/MeOH/AcOH (9/1/0.5); H NMR
(DMSO-d6) δ 1.30 (9H, s, tBu), 3.45 (2H, m, CH2OH), 4.51 (1H,
q, CHCH2OH), 4.27 (1H, br s, CH2OH), 7.30 (1H, d, BocNH),
7.37 (1H, t, Ar), 7.47 (1H, d, Ar), 7.75 (1H, d, Ar), 7.83 (1H, s,
Ar). Anal. (C14H19NO5) C, H, N.
P r ep a r a tion of 3-[(2SR)-2-(Boc-a m in o)-1-h yd r oxyeth -
yl]ben zam ide (27a) an d 3-[(2SR)-2-(Boc-am in o)-1-h ydr ox-
yeth yl]-N,N-d im eth ylben za m id e (27b). To a cold (-15 °C)
solution of 26 (1 equiv) in DMF were successively added
Meth yl (2SR)-4-(ter t-Bu tylsu lfa m oyl)-2-(Cbz-a m in o)-
bu ta n oa te (21). To a cold (0 °C) solution of (Z)-homocystine-
OMe (20) in MeOH (0.7 mL/mmol) and CCl4 (3.5 mL/mmol)
was bubbled Cl2 (gas) for 1 h32 in order to obtain methyl (2SR)-
2-(Cbz-amino)-4-(chlorosulfonyl)butanoate. To a solution of
the latter in CH2Cl2 (1.8 mL/mmol) was added tert-butylamine.
After evaporation and classical workup, the residue was
purified on a silica gel column, using cHex/CH2Cl2/EtOAc (5/
i
N-methylmorpholine (1.1 equiv) and BuOCOCl (1.1 equiv).
After 15 min, the precipitated N-methylmorpholine hydro-
chloride was removed by filtration. For preparation of 27a , a
solution of NH3 (2 M) in DME (60 equiv) was added at -15
°C. For preparation of 27b, a solution of dimethylamine (3
equiv) and triethylamine (3 equiv) in DMF was added at -15
°C. In both cases the mixture was stirred at room temperature
for 4 h. After evaporation in vacuo, the residue was washed
with H2O and brine, dried over Na2SO4, and evaporated in
vacuo. The product 27a was purified by flash chromotography
on a silica gel column, using CH2Cl2/MeOH/AcOH (9/1/0.5) as
eluent (46% yield): Rf ) 0.37 in CH2Cl2/MeOH/AcOH (9/1/0.5);
1H NMR (DMSO-d6) δ 1.31 (9H, s, tBu), 3.45 (2H, t, CH2OH),
4.50 (1H, q, CHCH2OH), 4.77 (1H, t, CH2OH), 7.20 (1H, d,
BOCNH), 7.28 (1H, s, CONH2), 7.32 (1H, d, Ar), 7.36 (1H, t,
Ar), 7.67 (1H, d, Ar), 7.76 (1H, s, Ar), 7.87 (1H, s, CONH2).
Anal. (C14H20N2O4) C, H, N.
The product 27b was purified by flash chromatography on
a silica gel column using CH2Cl2/MeOH/AcOH (9/1/0.5) as
eluent (68% yield): Rf ) 0.60 in CH2Cl2/EtOAc/AcOH (9/1/0.5);
1H NMR (DMSO-d6) δ 1.32 (9H, s, tBu), 2.85 (3H, s, CON-
(CH3)CH3), 2.93 (3H, s, CON(CH3)CH3), 3.45 (2H, d, CH2OH),
4.50 (1H, m, CHCH2OH), 7.17-7.34 (5H, m, Ar and BocNH).
Anal. (C16H24N2O4) C, H, N.
1
3/2) as eluent (77% yield): Rf ) 0.42 in AcEt/CH2Cl2 (1/9); H
NMR (DMSO-d6) δ 1.18 (9H, s, tBu), 1.88-2.13 (2H, m, CH2-
CH2SO2NH), 2.85-3.10 (2H, m, CH2SO2NH), 3.58 (3H, s,
COOCH3), 4.21 (1H, m, CHCOOMe), 4.99 (2H, s, CH2Ph), 6.86
(1H, s, NHtBu), 7.29 (5H, m, Ph), 7.85 (1H, d, BzlOCONH).
Anal. (C17H26N2O6S) C, H, N.
(3SR)-N-ter t-Bu t yl-3-(Cb z-a m in o)-4-h yd r oxyb u t a n e-
su lfon a m id e (22). The N-protected amino ester 21 (1 equiv)
was dissolved in EtOH/H2O (1/1). NaBH4 (4 equiv) was added,
and the mixture was heated at 50 °C for 6 h. The reaction
was stopped with 1 N HCl, and the mixture was extracted with
EtOAc. After classical workup, (3SR)-N-tert-butyl-3-(Cbz-
amino)-4-hydroxybutanesulfonamide was obtained (74% yield):
Rf ) 0.18 in MeOH/CH2Cl2 (4/96); 1H NMR (DMSO-d6) δ 1.20
(9H, s, tBu), 1.64-1.99 (2H, m, CH2CH2SO2NH), 2.90 (2H, t,
CH2SO2NH), 3.30 (2H, m, CH2OH), 3.50 (1H, m, CHCH2OH),
4.72 (1H, t, CH2OH), 4.97 (2H, d, CH2Ph), 6.76 (1H, s, NHtBu),
7.11 (1H, d, BzlOCONH), 7.29 (5H, m, Ph). Anal. (C16H26N2O5S)
C, H, N.
(3SR)-N-ter t-Bu tyl-3-(Cbz-a m in o)-4-(a cetylsu lfa n yl)bu -
ta n esu lfon a m id e (23). The thioacetylation of (3SR)-N-tert-
butyl-3-(Cbz-amino)-4-hydroxybutanesulfonamide was then
performed by a Mitsunobu reaction25 to afford (3SR)-N-tert-
butyl-3-(Cbz-amino)-4-(acetylsulfanyl)butanesulfonamide as a
white solid (60% yield): Rf ) 0.24 in Et2O/cyclohexane (75/25);
1H NMR (DMSO-d6) δ 1.17 (9H, s, tBu), 1.70-1.90 (2H, m,
CH2CH2SO2NH), 2.28 (3H, s, SCOCH3), 2.82 (1H, ABX J )
13.6 Hz, CHCH2SCOCH3), 2.89 (2H, t, CH2SO2NH), 3.03 (1H,
ABX J ) 13.6 Hz, CHCH2SCOCH3), 3.60 (1H, m, CHCH2-
SCOCH3), 4.98 (2H, s, CH2Ph), 6.80 (1H, s, SO2NH), 7.29 (5H,
m, Ph), 7.37 (1H, d, BzlOCONH). Anal. (C18H28N2O5S2) C,
H, N.
(3SR)-3-Am in o-4-su lfa n ylbu ta n esu lfon a m id e (24). The
deprotection of the sulfonyl group was performed as described
for compounds 1-5. Then, the cleavage of the trityl group41,42
was followed by HF treatment.47 (3SR)-3-Amino-4-sulfanylbu-
tanesulfonamide (24) was thus obtained as a yellow oil (98%
yield): 1H NMR (DMSO-d6) δ 2.00 (2H, m, CH2CH2SO2NH2),
2.73 (2H, m, CH2SH), 3.07 (2H, m, CH2SO2NH2), 3.30 (1H, m,
CHCH2SH), 6.85 (3H, brs, NH3+); SM (ES) (M + H)+ m/z )
185.4. Anal. (C4H12N2O2S2).
P r ep a r a tion of 3-[(2SR)-1-(Acetylsu lfa n yl)-2-(Boc-a m i-
n o)eth yl]ben za m id e (28a ) a n d 3-[(2SR)-1-(Acetylsu lfa -
n yl)-2-(Boc-a m in o)eth yl]-N,N-d im eth ylben za m id e (28b).
The free hydroxy compound 27a (respectively 27b) (1 equiv)
was dissolved in DMF (0.2 mmol/mL); then TEA (2.7 molar
equiv) and methanesulfonyl chloride were added at -10 °C.50
The reaction mixture was stirred at room temperature for 3
h. The DMF was evaporated, and the residue was taken up
in EtOAc and treated by classical workup. To a solution of
the mesylate (1 equiv) in DMF (5 mL/mmol) was added at 0
°C 3 equiv of potassium thioacetate. After stirring overnight
at room temperature and evaporation to dryness, the residue
was taken up in EtOAc, washed with water and brine, dried,
and evaporated in vacuo.
Com p ou n d 28a : Rf ) 0.21 in n-heptane/EtOAc/AcOH (5/
5/0.5) (71% yield); 1H NMR (DMSO-d6) δ 1.29 (9H, s, tBu), 2.27
(3H, s, SCOCH3), 2.97 (1H, dd, CH2SCOCH3), 3.15 (1H, dd,
CH2SCOCH3), 4.54 (1H, q, CHCH2SCOCH3), 7.33 (1H, s,
CONH2), 7.36 (1H, t, Ar), 7.42 (1H, d, Ar), 7.53 (1H, d, BocNH),
7.70 (1H, d, Ar), 7.80 (1H, s, Ar), 7.93 (1H, s, CONH2). Anal.
(C16H22N2O4S) C, H, N.
Com p ou n d 28b: Rf ) 0.21 in n-heptane/EtOAc/AcOH (5/
5/0.5) (38% yield); 1H NMR (DMSO-d6) δ 1.30 (9H, s, tBu), 2.28
(3H, s, SCOCH3), 2.83 (3H, s, CON(CH3)CH3), 2.90 (3H, s,
CON(CH3)CH3), 3.00 (1H, dd, CH2SCOCH3), 3.15 (1H, dd, CH2-
SCOCH3), 4.54 (1H, m, CHCH2SCOCH3), 7.19-7.38 (4H, m,
Ar), 7.53 (1H, d, BocNH). Anal. (C18H26N2O4S) C, H, N.
P r ep a r a tion of 3,3′-[(Disu lfa n ed iyl)bis((2SR)-2-a m in o-
eth ylen e)]bis(ben za m id e) (29a ) a n d 3,3′-[(Disu lfa n ed iyl)-
b is ((2S R )-2-a m in o e t h y le n e )]b is (N ,N -d im e t h y lb e n z-
a m id e) (29b). Deprotection of the acetyl and Boc groups of
compounds 28a ,b was obtained as described for compound 12.
Com p ou n d 29a : Rf ) 0.14 in CH2Cl2/MeOH/AcOH (5/5/0.5)
DL-Diet h yl (Boc-a m in o)-(3-ca r b oxyp h en yl)glycin a t e
(25). DL-(3-Carboxyphenyl)glycine, prepared as previously
described,27 was refluxed in EtOH with 5 equiv of SOCl2
(100%). The resulting compound was N-protected by a tert-
butyloxycarbonyl group with
a procedure previously de-
scribed48 to obtain DL-diethyl (Boc-amino)(3-carboxyphenyl)-
glycinate (25) using Boc2O, NEt3 in DMF (100% yield): Rf )
0.61 in EtOAc/heptane (1/1); 1H NMR (DMSO-d6) δ 1.07 (3H,
t, CHCOOCH2CH3), 1.26 (3H, t, C6H4COOCH2CH3), 1.33 (9H,
s, tBu), 4.04 (2H, q, CHCOOCH2CH3), 4.27 (2H, q, C6H4-
COOCH2CH3), 5.22 (1H, d, CHCOOCH2CH3), 7.46 (1H, t, Ar),
7.60 (1H, d, Ar), 7.85 (2H, d, Ar and BocNH), 7.93 (1H, s, Ar).
Anal. (C18H25NO6) C, H, N.
1
(82% yield); H NMR (DMSO-d6) δ 3.30 (2H, m, CH2S), 4.50