Peptide-Based Drug Design

228 Cudic and Stawikowski
approach for the synthesis of β-aminosulfonamides requires synthesis of
sulfonyl chlorides followed by coupling of an amino acid or peptide via amino
group and subsequent oxidation using an OsO4/N-methylmorpholine-N-oxide
(NMMO) mixture (27). The advantage of the sulfonyl chloride approach is
their relative high reactivity in the coupling reactions compared to the sulfonyl
chlorides, but the disadvantage is sulfonyl chloride’s limited stability and
requirements for the oxidation step after completion of the coupling reaction.
Therefore, preparation of sulfonyl chloride monomeric building blocks will not
be described in this chapter.
3.1.1.1. SULFONYL CHLORIDE SYNTHESIS
These protocols were adopted from refs. (21–23) and (28).
Reduction step:
1. To a cold (−15 ◦ C) solution of N-protected α-amino acid (10 mmol) in DME (10
mL) add NMM (10 mmol) and isobutyl chloroformate (10 mmol).
2. Remove precipitated N-methylmorpholine hydrochloride by filtration and wash it
with DME (5 × 2mL).
3. Combine washings in a large flask and cool to 0 ◦ C.
4. Add solution of NaBH4 (15 mmol) in water (5 mL) (see Note 1).
5. Add additional 250 mL of water.
6. If alcoholic product precipitates, collect precipitate by filtration and wash
thoroughly with water and hexane (see Note 2).
Mesylation step:
1. To a solution of alcohol (50 mmol) in DCM (150 mL) add Et3N (57 mmol).
2. Cool solution to 0 ◦ C and add dropwise methanesulfonyl chloride (57 mmol).
3. Stir reaction mixture overnight at room temperature.
4. Add 100 mL of DCM and wash the mixture with 5% NaHCO3 (2 × 100 mL),
water (2 × 100 mL), and saturated NaCl solution (80 mL).
5. Dry organic phase over Na2SO4, concentrate the filtrate, and purify by column
chromatography over silica gel (eluent: DCM/CH3OH = 9/1).
Thioacylation step:
1. Add thioacetic acid (51 mmol) to a suspension of Cs2CO3 (47 mmol) in DMF
(70 mL).
2. Add in one portion previously prepared mesylate (43 mmol).
3. Stir reaction mixture at 50 ◦ C for 24 h (see Note 3).
4. Pour reaction mixture in to water (250 mL) and extract with EtOAc (3 × 150 mL).
5. Combined organic layers wash with water (150 mL), 5% NaHCO3 (150 mL), and
saturated NaCl solution (150 mL).
6. Dry organic phase over Na2SO4, concentrate the filtrate and purify by column
chromatography over silica gel (eluent: EtOAc/hexane = 1/1).