Peptide-Based Drug Design

234 Cudic and Stawikowski
Fmoc-HN
R
O
O
Pd/C, THF, CHCl 3
1) Cl-OC-Oi Bu, NMM R
2) NaBH4/H2O Fmoc-HN
Fmoc-HN
R
NH 3 + Cl –
Cl
O
O
OH
DIPEA, DCM
PPh 3, DEAD, HN 3
NO 2
Fmoc-HN
R
Fmoc-HN
Fig. 5. Synthesis of Fmoc-protected urea building blocks.
These protocols were adopted from ref. (53).
Reduction step:
Fmoc-protected amino alcohols can be prepared according to the protocol
described in Subheading 3.1.1.1.
3.3.1.1. PREPARATION OF FMOC-PROTECTED AZIDES
1. To a cooled solution (0 ◦ C) of PPh3 (10 mmol) in THF (30 mL) add dropwise
DEAD (1 eq) under an inert atmosphere.
2. Add dropwise 1.5 M solution of HN3 in benzene (1 eq) (see Note 13).
3. Add in one portion Fmoc-protected amino alcohol (1 eq).
4. Stir reaction mixture overnight at room temperature.
5. Concentrate reaction mixture under vacuum and purify by column chromatography
over silica gel (eluent: EtOAc/hexane = 1/6).
3.3.1.2. ACTIVATION STEP
1. Dissolve azide in the mixture of THF (50 mL) and CHCl3 (1 mL), add 10% Pd/C
and stir overnight at room temperature under H2 atmosphere (1 bar).
2. After completion of hydrogenation, add water (4 mL) to reaction mixture to redissolve
precipitated material.
3. Filter reaction mixture over celite and evaporate the solvents.
4. Dry obtained product under vacuum over P2O5.
5. Add dry product (1 eq) and 4-nitrophenyl chloroformate (1.1 eq) to DCM.
6. Cool resulting suspension to 0 ◦ C (ice bath) and add dropwise solution of DIPEA
(2 eq) in DCM.
7. Stir reaction mixture for 30 min, then allow warming to room temperature and
continuing stirring for another 2 h.
8. Wash reaction mixture with 1 M KHSO4 (3x), water, and saturated NaCl
solution.
9. Dry organic phase dry over sodium sulfate, filter, and concentrate under
vacuum.
10. Purify crude product by column chromatography over silica gel (eluent:
EtOAc/hexane = 1/1).
H
N
O
O
R
N 3
NO 2