Convenient synthesis of disulfide substrates for trypanothione reductase using polymer-supported reagents

Article abstract of DOI:10.1016/S0040-4039(02)00064-3

Operationally simplified and high yielding methods for the preparation of N,N′-bis(benzyloxycarbonyl)-1-L-cysteinylglycyl-3- dimethylaminopropylamide disulfide, an alternative substrate for trypanothione reductase, and a structural analogue, using polymer

Full text of DOI:10.1016/S0040-4039(02)00064-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1587–1589
Convenient synthesis of disulfide substrates for trypanothione
reductase using polymer-supported reagents
Kelly Chibale,a,* Alex Chipelemea and Stuart Warrenb
aDepartment of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
bDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 6 November 2001; accepted 4 January 2002
Abstract—Operationally simplified and high yielding methods for the preparation of N,N%-bis(benzyloxycarbonyl)-1-L-cysteinyl-
glycyl-3-dimethylaminopropylamide disulfide, an alternative substrate for trypanothione reductase, and a structural analogue,
using polymer-supported reagents are described. © 2002 Elsevier Science Ltd. All rights reserved.
N,N% - Bis(benzyloxycarbonyl) - 1 -
L
- cysteinylglycyl - 3-
The synthesis of 1 was executed as depicted in Scheme
dimethylaminopropylamide disulfide 1 is a known alter-
native synthetic substrate for the anti-oxidative enzyme
trypanothione reductase (TryR).1 Unlike the natural
substrate trypanothione disulfide 2, compound 1 has
been used as a basis for non-reducible inhibitors of
TryR.2 Compound 1 has been synthesised, in 46%
overall yield, using solution phase chemistry.1 In spite
of the few steps involved in the reported synthesis of 1,
the isolation and purification of the products required
laborious and time-consuming chromatography.
1.
The starting point for the synthesis of 1 was the cou-
pling reaction of 7 (prepared from glycine and benzyl
chloroformate) and 3-N,N-dimethylaminopropylamine
according to the literature procedure.3 Activation of the
carboxyl group of 7 by P-EDC 4 in the presence of
3-N,N-dimethylaminopropylamine gave 8 in high yield
after filtration. Removal of the benzyloxycarbonyl
(Cbz) group by catalytic hydrogenation gave 9 in quan-
titative yield after filtration. Coupling of 9 and cystine
derivative 10 in the presence of 4 and 1-hydroxybenzo-
triazole (HOBT), followed by removal of HOBT using
5 as a scavenger6 and filtration gave 1 in 72% overall
yield.7
In this letter we report operationally simplified and high
yielding methods for the synthesis of 1 and its analogue
3 using polymer-supported reagents, 2% crosslinked
polystyrene beads containing di-imide residues 4,3
macroporous polystyrene anion-exchange beads con-
taining quaternary ammonium salt moieties 5 in the
carbonate form4 and 2% crosslinked polystyrene beads
containing N,N-dialkylaminopyridine residues 6.5
A similar strategy was employed for the synthesis of
analogue 3 (Scheme 2). The starting point was the
preparation of 12 using the coupling conditions
O
CO2H
O
H
H
N
H
N
CbzHN
N
NMe2
N
H
H2N
H2N
N
H
(CH2)3
NH
O
O
O
O
O
O
S
S
S
S
H
N
H
N
(CH2)4
CbzHN
N
H
NMe2
N
H
N
H
O
CO2H
O
1
2
* Corresponding author. Fax: +27 21 689 7499; e-mail: chibale@science.uct.ac.za
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00064-3

1588
K. Chibale et al. / Tetrahedron Letters 43 (2002) 1587–1589
O
Cl
N
O
O
N C NEt
H
4
CbzHN
CbzHN
N
NMe2
NMe2
N
H
O
O
NEt3+(CO3)2-
.
S
S
0 5
5
H
N
N
H
N
O
O
N
Me
O
6
3
employed in the last two steps for the synthesis of 1.
Compound 12 was treated with acetyl chloride in the
presence of the acylation catalyst 6 to furnish 13, which
was subjected to catalytic hydrogenation to afford 14 in
quantitative yield after filtration. In a similar fashion 14
was coupled with cystine derivative 10 to give 3 in 69%
overall yield.7
H
N
a
NMe2
CbzHN
CO2H
CbzHN
O
7
8
b
S)2
H
N
NMe2
H2N
In conclusion our strategy for the synthesis of 1 and its
analogue 3 using polymer-supported reagents proved to
be superior in terms of simplicity, efficiency and yields
in comparison to the reported solution phase synthesis.1
Coupled with the reported solid-phase syntheses of the
natural substrate,8–10 our approach to the synthesis of 1
should provide options for synthesising these disulfides
and related compounds.
+
CbzHN
CO2H
O
10
9
c
1
Scheme 1. Reagents and conditions: (a) 2.5 equiv. of 4, 1.0
equiv. of H2N(CH2)3N(CH3)2, CHCl3, 25°C, 16 h, filtration,
91%; (b) 10% Pd/C, H2, MeOH, 25°C, 2 h, filtration, 100%;
(c) 2.5 equiv. of 4, 1.0 equiv. of HOBT, CHCl3, 25°C, 16 h,
then 3.0 equiv. of 5, CH2Cl2, 25°C, 3 h, filtration, 79%.
General procedure for amide bond formation and removal
of HOBT. To a suspension of 4 [1.0 mmol of
chloromethylated poly(styrene-co-divinyl benzene), 2%
crosslinked, 1.4 mmol/g loading capacity] in chloroform
(10 ml), the acid (0.44 mmol) and amine (0.4 mmol)
were added. The reaction mixture was shaken for 24 h
at room temperature and then filtered. The resin was
washed with chloroform (3×5 ml) and the combined
filtrate was concentrated under reduced pressure. The
residue was re-dissolved in dichloromethane and then 5
[0.88 mmol of macroporous poly(styrene-co-divinyl
benzene), anion-exchange resin, 2.64 mmol/g loading
capacity] was added. The resultant mixture was shaken
at room temperature for 2 h, filtered, washed with
dichloromethane (3×5 ml) and concentrated to give the
product.
OH
CO2H
OH
H
N
a
NMe2
CbzHN
CbzHN
O
12
11
b
OAc
H
N
OAc
H
N
c
NMe2
NMe2
H2N
CbzHN
O
O
13
14
d
Acknowledgements
3
Financial support from the Wellcome Trust (grant no.
052075/Z/97/Z/JMW/JPS/CG) is gratefully acknow-
ledged.
Scheme 2. Reagents and conditions: (a) 2.5 equiv. of 4, 1.0
equiv. of H2N(CH2)3N(CH3)2, 1.0 equiv. of HOBT, CHCl3,
25°C, 16 h and then 3.0 equiv. of 5, CH2Cl2, 25°C, 3 h,
filtration, 96%; (b) 2.0 equiv. of AcCl, 4.0 equiv. of 6,
CH2Cl2, 25°C, 12 h, filtration, 97%; (c) 10% Pd/C, H2,
MeOH, 25°C, 2 h, filtration, 100%; (d) 2.5 equiv. of 4, 2.0
equiv. of 10, 1.0 equiv. of HOBT, CHCl3, 25°C, 16 h and then
3.0 equiv. of 5, CH2Cl2, 25°C, 3 h, filtration, 74%.
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