Peptide-Based Drug Design

Peptidomimetics 229
Oxidation step:
1. Add a mixture of 30% H2O2 (30 mL) and AcOH (60 mL) to a solution of thioacetate
(34 mmol) in AcOH (30 mL).
2. Stir reaction mixture for 24 h at room temperature.
3. Add 10% Pd/C (see Note 4).
4. Filter resulting mixture through celite, concentrate the filtrate, and co-evaporate
with toluene and diethyl ether in order to remove traces of AcOH.
5. Resulting product can be used in the next step without further purification.
Chlorination step:
1. To a cooled (ice bath) mixture of protected sulfonic acid (18 mmol), add excess of
SOCl2 (10 mL), add dropwise DMF (1 mL).
2. Remove the ice bath.
3. Stir reaction mixture at reflux for 5 h.
4. Remove chlorinating reagents by evaporation, followed by co-evaporating with
toluene and diethyl ether.
5. Dissolve the residue in EtOAc (100 mL) and wash with water (60 mL), saturated
NaHCO3 (60 mL), and saturated NaCl solution (50 mL).
6. Dry organic phase over Na2SO4, concentrate the filtrate, add DCM and purify by
filtration through a short pad of silica gel.
3.1.2. Solid-Phase Peptidosulfonamide Synthesis
For the synthesis of peptidosulfonamides, especially long and complex ones, a
solid-phase methodology is indispensable (Fig. 3). Literature reports on methods
for solid-phase synthesis of peptidosulfonamides include both sulfonyl- (17,18)
and sulfinyl chloride amino acid analog couplings (20,27).However,thesulfinyl
chloride method turned out to be inferior mainly because the yield of peptidosulfinamide
oxidation to corresponding peptidosulfonamide strongly depends
on the peptidomimetic sequence and the type of resin used in the synthesis.
Sulfinyl chloride methodology therefore represents an attractive approach for the
synthesis of very short peptidosulfonamides rather than a general methodology
for solid-phase synthesis of these peptidomimetics.
This protocol was adopted from refs. (17) and (18):
1. Place resin in dry reaction vessel.
2. Remove the Fmoc protecting group by agitating the resin with 20% piperidine in
NMP (3 × 10 min).
3. Wash resin with NMP (25 mL/mmol, 5 × 2 min) and DCM (25 mL/mmol, 5 ×
2min)(see Note 5).
4. Dissolve Fmoc-aa-�(CH2SO2)-Cl (4 eq) and NMM (6 eq) in DCM
(15 mL/mmol). Add this solution to the resin.
5. Allow the resin to agitate at room temperature for 3 h.